REVIEW
published: 23 August 2021
doi: 10.3389/fendo.2021.700884
Motilin Comparative Study:
Structure, Distribution, Receptors,
and Gastrointestinal Motility
Takio Kitazawa 1* and Hiroyuki Kaiya 2
1
2
Edited by:
Masayasu Kojima,
Kurume University, Japan
Reviewed by:
Elisa L. Hill-Yardin,
RMIT University, Australia
Joao Carlos dos Reis Cardoso,
University of Algarve, Portugal
*Correspondence:
Takio Kitazawa
tko-kita@rakuno.ac.jp
Specialty section:
This article was submitted to
Neuroendocrine Science,
a section of the journal
Frontiers in Endocrinology
Received: 27 April 2021
Accepted: 16 July 2021
Published: 23 August 2021
Citation:
Kitazawa T and Kaiya H (2021) Motilin
Comparative Study: Structure,
Distribution, Receptors, and
Gastrointestinal Motility.
Front. Endocrinol. 12:700884.
doi: 10.3389/fendo.2021.700884
Comparative Animal Pharmacology, Department of Veterinary Science, Rakuno Gakuen University, Ebetsu, Japan,
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
Motilin, produced in endocrine cells in the mucosa of the upper intestine, is an important
regulator of gastrointestinal (GI) motility and mediates the phase III of interdigestive
migrating motor complex (MMC) in the stomach of humans, dogs and house musk
shrews through the specific motilin receptor (MLN-R). Motilin-induced MMC contributes
to the maintenance of normal GI functions and transmits a hunger signal from the stomach
to the brain. Motilin has been identified in various mammals, but the physiological roles of
motilin in regulating GI motility in these mammals are well not understood due to
inconsistencies between studies conducted on different species using a range of
experimental conditions. Motilin orthologs have been identified in non-mammalian
vertebrates, and the sequence of avian motilin is relatively close to that of mammals,
but reptile, amphibian and fish motilins show distinctive different sequences. The MLN-R
has also been identified in mammals and non-mammalian vertebrates, and can be divided
into two main groups: mammal/bird/reptile/amphibian clade and fish clade. Almost 50
years have passed since discovery of motilin, here we reviewed the structure, distribution,
receptor and the GI motility regulatory function of motilin in vertebrates from fish
to mammals.
Keywords: motilin, motilin receptor, gastrointestinal contractility, enteric nerves, smooth muscle, vagus afferent
nerves, comparative biology
INTRODUCTION
Motilin was identified in the 1970s from the mucosa of the porcine upper intestine as a stimulant of
gastric motility (1–3). Brown and colleagues examined the effects of duodenal alkalinization on
pressure of the gastric pouch and found that alkalinization caused an increase in pressure of the
pouch. Since the pouch was isolated from the autonomic nerves, it was thought that alkalinization
induced the release of substances from the duodenal mucosa that stimulate motility. Duodenal
extracts of pigs were examined for their gastric motor-stimulating activity, and motilin was
separated as a distinct polypeptide. Porcine motilin was found to be a 22-amino acid peptide
with a primary sequence of FVPIFTYGEL QRMQEKERNKGQ (1–3). Later, the presence of motilin
was shown, and its sequence was determined in rabbits (Leporinae Trouessart), humans (Homo
sapiens), dogs (Canis lupus familiaris), cats (Felis silvestris catus), cows (Bos taurus) and sheep (Ovis
aries). Although there are some differences in amino acid sequence, the N-terminal sequences are
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Comparative Study for Motilin Function
interdigestive state with three phases: phase I (motor quiescent
period), phase II (irregular and low-amplitude contraction period)
and phase III (regular and high-amplitude contraction period)
(6, 13–16). The function of MMCs is thought to include flushing
out of the GI lumen mechanically and chemically for preventing
bacterial overgrowth and receiving next meals (6, 17). After
feeding, the cyclic motility pattern is suddenly disrupted and
changed into irregular phasic digestive contractions, the
amplitudes of which are close to those in the phase II. The
duration of digestive contractions is more than 16 h and at
highly conserved among mammals (4–7) (Table 1). Curiously, in
an early study, motilin did not cause contractions of rat and
guinea-pig GI tract (9), and later molecular studies indicated the
lack of motilin and/or its receptor in rodents including mice (10–
12). Inability of the rodents for motilin study is one of the
obstacles for performing extensive physiological studies on the
functions of motilin.
GI motility patterns of the interdigestive and digestive periods
are quite different for each mammal. A cyclic increase of GI
motility called migrating motor complex (MMC) occurs in the
TABLE 1 | Representative information on motilin in various vertebrates.
Scientific name
Mammals
Homo sapiens
Bos taurus
Canis lupus familiaris
Cavia porcellus
Sorex araneus
Monodelphis domestica
Equus caballus
Sus scrofa
Oryctolagus cuniculus
Suncus murinus
Felis catus
Macaca mulatta
Ovis aries
Birds
Lonchura striata domestica
Gallus gallus
Aquila chrysaetos chrysaetos
Coturnix japonica
Apteryx rowi
Phasianus colchicus
Columba livia
Meleagris gallopavo
Reptiles
Alligator mississippiensis
Crocodylus porosus
Anolis carolinensis
Python bivittatus
Pogona vitticeps
Podarcis muralis
Pelodiscus sinensis
Chelonia mydas
Amphibians
Cynops pyrrhogaster
Ambystoma mexicanum
Cynops pyrrhogaster
Pleurodeles waltl
Fish
Gadus morhua
Latimeria chalumnae
Cyprinus carpio
Oryzias latipes
Oncorhynchus mykiss
Lateolabrax maculatus
Takifugu rubripes
Danio rerio
Labrus Bergylta
Common name
NCBI Transcript #
NCBI Protein #
Mature motilin sequence
Human
Cattle
Dog
Domestic guinea pig
European shrew
Gray short-tailed opossum
Horse
Pig
Rabbit
House musks shrew
Domestic cat
Rhesus monkey
Sheep
NM_002418
XM_010818020.3
XM_022425739
NM_001172860.2
XM_004617716
XM_007483690.2
XM_023624006
NM_214235
NM_001101699
AB325968
NM_001009278
NM_001032807
NM_001009439
NP_002409
XP_010816322
XP_022281447
NP_001166331.2
XP_004617773
XP_007483752
XP_023479774
NP_999400
NP_001095169
BAI66099
NP_001009278
NP_001027979
NP_001009439
FVPIFTYGELQRMQ–EKERNK-GQ
FVPIFTYGEVQRMQ–EKERYK-GQ
FVPIFTHSELQKIR–EKERNK-GQ
FIPIFTYSELRRTQ–EREQNK-GL
FVPIFTHSELQRMQ–EKEQNK-GR
FVPIFTYSDVQRMQ–EKERNK-GQ
FVPIFTYSELQRMQ–EKERNR-GQ
FVPSFTYGELQRMQ–EKERNK-GQ
FVPIFTYSELQRMQ–ERERNR-GH
FMPIFTYGELQKMQ–EKEQNK-GQ
FVPIFTHSELQRIR–EKERNK-GQ
FVPIFTYGELQRMQ–EKERSK-GQ
FVPIFTYGEVQRMQ–EKERYK-GQ
Bengalese finch
Chicken
Golden eagle
Japanese quail
Okarito brown kiwi
Ring-necked pheasant
Rock pigeon
Turkey
XM_031506971
NM_001305129
XM_030000337
XM_015885100.2
XM_026056740
XM_031605951
XM_021281156
XM_010724334.3
XP_031362831
NP_001292058
XP_029856197
XP_015740586
XP_025912525
XP_031461811
XP_021136831
XP_010722636
FMPFFTQSDFQKMQ–EKERNKAGQ
FVPFFTQSDIQKMQ–EKERNK-GQ
FVPFFTKSDFQKMQ–EKERNKGGQ
FVPFFTQSDFQKMQ–EKERNK-GQ
FLPFFTQSDFRKMQ–EKERNK-GQ
FVPFFTQSDIQKMQ–EKERIK-GQ
FVPFFTQSDRFKMQLQEKERNKAGQ
FVPFFTQSDIQKMQ–EKERIK-GQ
American alligator
Australian saltwater crocodile
Green anole
Burmese python
Central bearded dragon
Common wall lizard
Chinese soft-shelled turtle
Green sea turtle
XM_019484898
XM_019546714
XM_008109785
XM_015889024.2
XM_020794918
XM_028732029
XM_014571642.2
XM_027825953.2
XP_019340443
XP_019402259
XP_008107992
XP_015744510
XP_020650577
XP_028587862
XP_014427128.2
XP_027681754
FLPIFTHSDMQRMQ–ERERNK-GQ
FLPIFTHSDIQRMQ–ERERNK-GQ
YTAFFTREDFRKMQ–ENEKNK-AQ
YLAFYSREDFRRMQ–EKEKNP-TQ
YTALYSWEDFRRMQ–ERERNQ-AQ
YLAFYTPDDFRKMQ–EKERNR-AQ
YLAFFTRSDIERMQ–ERERNK-AQ
YLAFFTRSDIERMQLQEKERNK-AQ
Gaboon caecilian
Axolotl
Japanese fire belly Newt
Iberian ribbed newt
XM_033918405
XP_033774296
YISFVSHNDATKMK–DRERNR-LQ
FLPIFTISESMRMQ–EKMRNN-AM
FLPIFSPSDARRMQ–ERERNK-GM
FLPIFSPSDARRMQ–AKEKNR-AM
Atlantic cod
Coelacanth
Common carp
Japanese medaka
Rainbow trout
Spotted sea bass
Torafugu
Zebrafish
Ballan wrasse
XM_030375104
XM_005995467
LN590830
XM_023955013
XM_036984493
MH046054
XM_029826583
NM_001386353
XP_030230964
XP_005995529
HITFFSPREMMLM——KERDa#
FISFFSPSDMRRM–MEKEKSKALa
HIAFFSPKEMREL–REKEa
HITFFSPKELLHM–RLQEQQEf##
HFSFFSPKEMREM–KALQNKLa
HITFFSPKEMMLM——KEREa
HITFFSPKEMMVL——KQEQEa
HIAFFSPKEMREL——REKEa
HITFFSPKEMMLM——KEREa*
XP_023810781
XP_036840388
AZM68775
XP_029682443
NP_001373282
Amino acids that differ from the human sequence are shown in red. The guinea pig genes shown in green is considered to be pseudogenized.
#, ## The small letter "a" and "f" indicate the C-terminal amidated and hydroxyl ternimi, respectively.
*Motilin structure is obtained from Zhou et al. (8)
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and motilin-ip cells were detected in the duodenum but not in
the proventriculus and gizzard of chickens (Gallus gallus
domesticus, 33) and quails (Coturnix japonica, 34). Motilin-like
immunoreactivity was detected in some reptiles (Caiman
latirostris, Caiman crocodilus, Egernia kingii) but not in other
reptiles (Testudo graeca, Mauremys capsica, Lacetra lepida,
Alligator mississippiensis) or fish (Tinca tinca, Ctenopharyngodon
idellus) (35–40). Because antibodies against human motilin were
used in these studies, the sequence similarity with human motilin
in these animals was suggested.
the end, phase III-like contractions occur to completely remove
the intraluminal contents, and GI motility changes into the
interdigestive pattern (18). The well-known function of motilin is
the GI motility activation of the stomach, small intestine and colon,
and a typical example is the mediation of phase III of the gastric
MMC in a fasting state in humans, dogs, and house musk shrews
(Suncus murinus called Suncus) (6, 13–16, 19, 20). However, actions
of motilin on motility of other digestive organs, such as the lower
esophageal sphincter, gallbladder have been reported. In addition,
other physiological effects of motilin on stimulation of gastric acid,
pepsinogen, insulin and growth hormone release, and on food
intake have also been reported (see another Section).
Motilin-induced actions are mediated by a G protein-coupled
receptor (GPCR), GPR 38, called the motilin receptor (MLN-R),
and which is mainly located on enteric neurons and smooth
muscle cells of the GI tract in addition to its expression in the GI
mucosa (21, 22). The presence of MLN-Rs in the central nervous
system (CNS) has been also indicated (5, 23, 24).
The existence of motilin and its receptors in non-mammalian
vertebrates such as birds, reptiles, amphibians, and fish has been
demonstrated by identification of those mRNAs (Figure 1,
Table 1), and comparative biological studies have been
performed to clarify the functions of motilin in GI motility of
these animals.
In this review, we focus on the results of biochemical,
immunohistochemical and functional studies regarding motilin
and MLN-Rs, and the roles of motilin in regulation of GI motility
in mammals and non-mammalian vertebrates.
Transcript Distribution
The highest expression of motilin precursor mRNA is seen in the
duodenum of mammals, such as humans (41), monkeys (Macaca
mulatta) (42), cats (Felis catus) (43), Suncus (44). Motilin
precursor mRNA expression has not been investigated in the
GI tract of birds, reptiles and amphibians. In fish, motilin
precursor mRNA expression has been detected in the GI tract
(8, 45). Brain such as the hypothalamus, hippocampus and
cerebellum is an extra-intestinal expression of motilin
precursor mRNA in some mammals (5, 42, 43).
CHARACTERIZATIONS OF MOTILIN
SEQUENCE ON VERTEBRATES
Mammals
After the discovery of porcine motilin, motilin was isolated and
its sequence was determined in humans (5, 46), rabbits (47), dogs
(48), cats (49), monkeys (42), sheep (4) and Suncus (44). Table 1
shows a comparison of the amino acid sequences in various
vertebrates. Mammalian motilin is composed of 22-amino-acid
residues. Structure-function relationship studies examined
contraction and binding affinities of motilin fragments
indicated the presence of three distinct regions in the motilin
sequence, and these regions were suggested to have different
functions. An in vitro study on rabbit duodenum contractile
activity and displacement of [125I]-motilin binding in the rabbit
antral membrane indicated that the N-terminal [1-7] is the
minimum basic structure for binding and biological activity,
the transit region [8-9] connects the N-terminal and C-terminal
regions, and the C-terminal [10-22] forms an a-helix to stabilize
the binding of the N-terminal and MLN-Rs (50, 51). On the
other hand, an in vivo study in which GI motility was measured
in conscious dogs indicated that the N-terminal is important for
eliciting biological activities and that the middle and C-terminal
portions are essential for preventing from the enzyme
degradation (51). Although there are some differences in the
sequence among mammals, the N-terminal region, which
corresponds to the position at 1-7 (FV(M)PIFTY(H)) and the
C-terminal region corresponding to the position at 14-18 (Q(R)
EK(R)ER(Q) are highly conserved (Table 1).
It has been reported in rodents such as rats and mice that the
motilin gene is pseudogenized (it used to code and generate
motilin, but now it has lost the ability to produce motilin) (10).
However, the motilin gene was deposited in the guinea-pig
DISTRIBUTION OF MOTILIN
Peptide Distribution
Immunohistochemical approaches with human motilin-specific
antiserum indicated that motilin-immunopositive (ip) cells are
scattered in the mucosa of the upper intestine as open-type in
humans (25), dogs (26), rabbits (Leporinae Trouessart, 27), sheep
(Ovis aries, 28) and cattle (Bos taurus, 29). An open-type cell
means that the endocrine cell is exposed to intestinal lumen and
is activated by luminal chemicals including pH, whereas a closetype cell is a cell that is surrounded by other mucosal cells. In
rabbits, motilin-ip cells are also found in the mucosa from the
gastric antrum to distal colon, and the number of positive cells is
the highest in the duodenum, moderate in the jejunum and low
in other regions (27). In rodents, motilin-ip cells in the rat
(Rattus norvegicus) intestine has been controversial: Smith et al.
(30) failed to detect the motilin-ip cells for the human motilin
antibody, whereas Vogel and Brown (31) and Sakai et al. (32)
demonstrated the motilin-ip cells in the rat GI tract using antihuman and anti-chicken motilin antibodies, respectively. Recent
genome-wide analyses have revealed that motilin and its receptor
genes are pseudogenized in rodents including rats (10, 12). This
discrepancy suggests that there are some systemic issues with
immunohistochemical studies.
Immunohistochemical studies for non-mammalian
vertebrates have shown by using anti-human motilin serum,
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Comparative Study for Motilin Function
FIGURE 1 | Molecular phylogenetic analysis of motilin receptor in vertebrates. The evolutionary history was inferred by using the Maximum Likelihood method based
on the JTT matrix-based model. The tree with the highest log likelihood (-7475.17) is shown. The percentage of trees in which the associated taxa clustered together
is shown next to the branches. Initial tree(s) for the heuristic search were obtained automatically by applying Neighbor-Join and BioNJ algorithms to a matrix of
pairwise distances estimated using a JTT model, and then selecting the topology with superior log likelihood value. The tree is drawn to scale, with branch lengths
measured in the number of substitutions per site. The analysis involved 33 amino acid sequences. All positions containing gaps and missing data were eliminated.
There were a total of 264 positions in the final dataset. Evolutionary analyses were conducted in MEGA7.
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(Table 1). Reptiles are divided into four orders: Testudines
(turtles), Sphenodontia and Squamata (lizards and snakes) and
Crocodilia (alligators). In mammalian and avian motilins, the
amino acid at the N-terminal end begins with phenylalanine(F),
but this depends on species in reptiles, i.e., alligator has F, but
turtle, snake and lizard have tyrosine(Y). Homology between
alligator/crocodile and human motilins is relatively high (73%),
but those between turtle and human motilins, and between snake
and human motilins are only 50% and 36%, respectively,
suggesting that the motilin genes would have diverged
dramatically in reptiles. Alligators are reptiles that are closely
related to avian species (53) and that may be a reason for the high
similarity of motilin sequence among mammals, birds and
alligators. As seen in avian motilins, also in reptile motilin, the
homology of the C-terminal region is high (from 58% to 92%)
compared with the homology of the N-terminal region (snake,
0%; lizard, 10%; turtle, 20%; alligator, 50%). This high similarity
of the C-terminal region of motilin, what does it mean? Because
the N-terminal region is considered to be essential for motilin
biological activities in dogs and rabbits (50, 54), low homology of
the N-terminal region in reptiles might affect the biological
activity in the mammalian GI tract. In fact, we found that
turtle and alligator motilins cause contraction of the rabbit
duodenum, but the affinity and amplitude of turtle motilin are
considerably low compared with those of alligator, chicken, and
human motilins (Figure 2A). This indicates the significance of
the N-terminal sequence for GI-stimulating activity of motilin
in mammals.
Amphibians consist of anura, urodela and dermophiidae
orders. There has been no reports for identification of motilin,
but we recently found urodelan newt motilin sequence by a
BLAST search of a database in the Japanese fire belly newt (fire
belly newt, Cynops pyrrhogaster) (http://antler.is.utsunomiya-u.
ac.jp/imori/) and Iberia newt (Pleurodeles waltl, http://www.
(Cavia porcellus), and its sequence has been estimated
(FVPIFTYSEL RRTQEREQNKRL, 52). We attempted to reexamine the existence of the motilin gene (11). In our search of
the Ensembl genome data, a guinea-pig motilin mRNA sequence
encoding a 121-amino-acid precursor (ENSCPOT00000008024)
was found, and a deduced mature sequence was estimated to be
FIPIFTYSEL RRTQEREQNKGL (11, Table 1), in which two
amino acids were different from that of Xu et al. (52). We tried
to detect those transcripts using several primers sets, however, it
could never be amplified (11), concluding pseudogenization of the
motilin gene in guinea-pigs.
Non-Mammals
Motilin has been identified in several avian species. Motilins of
chicken, turkey (Meleagris gallopavo) and pheasant (Phasianus
colchicus versicolor) and kiwi (Apteryx rowl) consist of 22 amino
acids as in mammals, whereas the Bengalese finch (Lonchura
striata domestica) and Golden eagle (Aquila chrysaetos
chrysaetos) have 23 amino acids, and Rock pigeon (Columba
livia) has 25 amino acids (Table 1). Motilins in Galliformes
including chickens, pheasants, turkeys, and quails show a high
homology with chicken motilin with a difference in only one
amino acid. Three amino acids in finch and kiwi motilins are
different from those in chicken motilin (Table 1). Therefore
motilin sequences in avian species are highly conserved
compared with those in mammals with diversified motilin
sequences. When the motilin sequence of birds is compared
with that of humans with focus on the N-terminal [1-10] and Cterminal [11-22], the homology of the C-terminal is high (from
83% to 92%) compared with the homology of the N-terminal
(from 40 to 50%), suggesting a functional significance of
conserved C-terminal sequence (Table 1).
Motilin in reptiles is also composed of 22 amino acids but it
has a different amino acid at position 1 of the N-terminal
A
B
C
FIGURE 2 | Comparison of contractile efficacy of different vertebrate motilins in isolated muscle strips from rabbit duodenum, chicken ileum and Japanese fire belly
newt stomach. Isolated GI muscle strips from each animal were incubated in an organ bath containing bubbled physiological salt solution. Motilins were applied in
the organ bath and evoked muscle contractions were measured by a force-transducer. Using this equipment, GI muscle-contracting actions of human, chicken,
alligator, turtle, newt and zebrafish motilins were compared in the isolated rabbit duodenum (A), chicken ileum (B) and Japanese fire belly newt stomach (C). The
symbols indicate concentration-response curves for the six motilins (human, chicken, alligator, turtle, newt and zebrafish). The Y axis indicates the relative amplitude
of contraction normalized by the response of 10-4 M acetylcholine. Each symbol indicates the means ± SEM of results of at least five experiments. Homologous
motilin showed the strongest response in respective GI strips (rabbit duodenum vs. human motilin; chicken ileum vs. chicken motilin; newt stomach vs. newt motilin).
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nibb.ac.jp/imori/main/) (Table 1). The motilin sequences of the
fire belly newt and Iberia newt consist of 22 amino acids and are
the same at the N-terminal [1-14]. The N-terminal sequence
(FLPIF) is identical to that of alligators and is close to that of
humans (FVPIF). We also searched axolotl database
(Ambystoma mexicanum, http://ambystoma.uky.edu:4567), and
found that the homology of fire belly newt and axolotl motilins to
human motilin was 59% (13 of 22 amino acids being same). On
the other hand, Gaboon caecilian (Geotrypetes seraphini), a
species of amphibian (dermophiidae) has a different sequence
from those of axolotl and newt, and the amino acid at the Nterminal end begins with tyrosine(Y) as seen in turtle, snake, and
lizard (Table 1). Homology of amphibian motilin to human
motilin is higher in the C-terminal [11-22] sequence (42-57%)
than that of N-terminal [1-10] sequence (0-50%) as with avian
and reptile motilins. We tried to examine the contractile activity
of newt motilin in isolated rabbit duodenum and chicken ileum
and found that newt motilin induced a small contraction in the
rabbit duodenum but no response in the chicken ileum
(Figure 2), while newt motilin showed a high responsiveness
in the newt stomach (Figure 2). These results suggest that
binding affinity of amphibian motilin to mammalian and avian
MLN-Rs is very low due to the critical sequence differences, and
amphibian motilin has an ability to bind MLN-R and to cause GI
contraction of amphibians itself.
Motilin peptides have been identified in various fish, and their
amino acid sequences are quite different from those of other
vertebrates (Table 1). The N-terminal end of motilin in most fish
begins with histidine (H), and the amino acid sequence varies
from 17 to 21 residues depending on the species. The N-terminal
[1-10] of fish motilin is well conserved. When the sequence was
compared with human motilin, the homology of the N-terminal
[1-10] region is 20% and that of the total sequence is only 24% (4
of 17 amino acids). Intriguingly, motilin sequence of the
coelacanth (Latimeria chalumnae), relative of tetrapod, is
different from other fish motilins: the coelacanth motilin
consists of 22 amino acids as in most vertebrates and starts
with phenylalanine (F) as birds and mammals (Table 1). It may
be that the molecules retain vestiges of the process of evolving
into land animals.
have a function other than stimulation of GI motility mediated
by the N-terminal. C-terminal portion is thought to form a-helix
and to stabilize the binding of motilin molecule with MLN-R and
to prevent its degradation by enzymes (50, 51), and it has been
reported to contribute enhancement of desensitization,
phosphorylation, and internalization of MLN-R (55), probably
due to formation of stable binding to MLN-R. Possibility of other
unknown functions of the C-terminal conservation of motilin
cannot be ruled out.
MOTILIN RECEPTOR
Agonists and Antagonists
At the beginning of motilin study, radioligand binding studies
showed the presence of high affinity binding sites saturated by
motilin in membrane preparations from human, rabbit, cat and
canine GI tracts and this binding site was proposed as the MLNR (56–60). In the GI tract, MLN-Rs were thought to be present
on both muscle cells and enteric neurons (56, 57, 60).
Erythromycin, a commonly used macrolide antibiotic, has
been known to have GI side effects (vomiting and diarrhea) (61).
Itoh et al. (62) and Inatomi et al. (63) reported that erythromycin
and its derivative caused GI contraction of the conscious dogs
similar with motilin. In vitro studies also indicated that
erythromycin contracted the rabbit duodenum as did motilin
(64, 65). Binding studies clearly indicated that erythromycin
bound to MLN-R and displaced a labelled motilin binding (64,
66, 67). Therefore, it was thought that macrolide antibiotics
including erythromycin could bind to MLN-Rs and acted as
motilin agonists causing GI contractions. These compounds are
termed motilide from the two words “motilin” and “macrolide”.
In early physiological studies, anti-motilin serum or motilininduced MLN-R desensitization was used to confirm
involvement of motilin, but those approaches also caused nonspecific actions. Therefore, the need for specific antagonists for
the MLN-R has increased to perform detailed physiological
studies. In 1995, two MLN-R antagonists, [Phe 3 , Leu 13 ]
porcine motilin and GM109, were reported (68, 69). Later,
MA2029, a 10-times potent and selective MLN-R antagonist
was also reported (70). Using these MLN-R antagonists,
involvement of endogenous motilin in the phase III of gastric
MMC initiated in fasted dogs or Suncus was confirmed (71, 72).
Summary of Structural Characterizations
of Motilin
A highly conserved N-terminal sequence starts with
phenylalanine (F) is thought to be essential for biological
activity in mammalian/avian motilins. Reptile motilin is just in
the transition stage to mammalian/avian type. In alligators,
lineage of reptile motilin may have evolved under different
evolutionary pressures to modify sequence of motilin close to
the mammalian/avian type. On the other hand, sequences of fish
and amphibian motilins quite differ from those of mammalian/
avian motilins. In the molecular evolution of motilin, there may
have been a major event at the time the reptiles emerged.
Comparison of sequence of vertebrate motilin indicates that
C-terminal sequence is more markedly conserved than that of
the N-terminal sequence. It suggests that the C-terminal might
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Structural Characteristics of MLN-R
In Vertebrates
The molecular structure of MLN-R was first identified in the
human stomach as an orphan GPCR (GPR38) (66, 73). GPR38 is
highly expressed in the human duodenum and colon. A study
using mutants of MLN-R indicated that motilin and
erythromycin share a common binding site in the third
transmembrane (TM3) region (74). A photoaffinity labeling
study also indicated that the first and second extracellular loop
domains located close to TM3 are important for binding of
motilin (75).
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Because many studies have been performed using dog and
rabbit GI tracts, MLN-R cloning has firstly been conducted in
these animals. The homologies of the deduced dog and rabbit
MLN-Rs to the human MLN-R are 84% and 71%, respectively
(76, 77). Later, Suzuki et al. (78) reported the Suncus MLN-R,
and showed high homology (76%) to the human MLN-R, and
the affinity of the Suncus MLN-R for MLN-R agonists was
comparable to that of the human MLN-R.
The amino acid sequence of the human MLN-R showed a
relatively high homology with that of growth hormone
secretagogue receptor 1a (ghrelin receptor) of humans (52%)
and Suncus (42%) (66, 78). When the amino acid sequences of
seven transmembrane domains were compared, the homology
between human MLN-R and ghrelin receptor further increases
(86%). Therefore, MLN-R is considered to be a sister receptor
with ghrelin receptor (79).
However, ghrelin cannot activate MLN-R of the rabbit
stomach (80), canine or human MLN-Rs expressed on CHO
cells (77). In an in vivo study with dogs, it was found that the
ghrelin decreased the phase III of gastric MMC different from the
action of motilin (14). Inconsistent of actions induced by ghrelin
and motilin suggests that motilin cannot stimulate the ghrelin
receptor, although there is some amino acid sequence similarity
in the two receptors. Similarly ghrelin also cannot act on MLN-Rs.
In research for non-mammalian MLN-Rs, Yamamoto et al.
(81) firstly characterized the chicken MLN-R identified in the
duodenum. The chicken MLN-R consists of 349 amino acids and
showed 59% sequence identity to the human MLN-R. The
chicken MLN-R expressed on HEK293 cells responded to
human and chicken motilins, but chicken motilin has higher
affinity than human motilin as was shown in an in vitro
contraction study (82). The low homology of the chicken
MLN-R to the human MLN-R might explain the low
contractile affinity of human motilin (Figure 2), and the
ineffectiveness of erythromycin or MLN-R antagonists (GM109
and MA2029) (82, 83). In amphibians, human motilin causes a
contraction of the upper intestine of the bullfrog and tropical
clawed frog (Xenopus tropicalis) and of the stomach of the black
spotted pond frog (Pelophylax nigromaculatus) (84, 85),
suggesting the presence of MLN-Rs in GI tract at least in these
frogs. Erythromycin and GM109 were ineffective in the bullfrog
intestine, suggesting a different structure of amphibian MLN-R
from the human MLN-R (85). In the Ensembl database search,
we found a candidate MLN-R for the tropical clawed frog
(ENSXET00000013318), but its ligand, endogenous motilin,
could not be found (Table 1). This indicates that anuran
amphibians have lost only motilin for some reason during
their evolution without losing the MLN-R. The retained MLNR is thought to function for exogenous motilin. Another
endogenous agonist may be acting on this MLN-R.
The zebrafish and spotted sea bass MLN-Rs have been
reported (8, 45). Zebrafish MLN-R consists of 345 amino acids
and shares 47% identity to the human MLN-R. The zebrafish
MLN-R expressed on HEK293 cells was activated by
homologous zebrafish motilin with an increased intracellular
Ca2+ concentration, whereas human motilin did not activate at
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least at a concentration of 100 nM (86). This indicates a strong
species-specific relationship of the ligand-receptor interaction in
the fish motilin system, and this can be expected from the
sequence of motilin, which is unique to fish.
Phylogenetic Tree of MLN-R in
Vertebrates
The phylogenic tree created by amino acid sequence of MLN-Rs
indicates two main branches have evolved: one group (group A)
is composed of tetrapods including mammalian, avian, reptile
and amphibian MLN-Rs and the other group (group B) contains
fish MLN-Rs (Figure 1). Group A can be divided into two clades:
terrestrial (mammals, birds and reptiles) type and semi-aquatic
(amphibian) type. The clade of the avian/reptile MLN-Rs can be
further divided into three, and alligator/crocodile MLN-Rs is
included in the same umbrella with the avian clade, as in the case
of motilin structure. Group B may have characteristics that
match the aquatic inhabiting nature of fish.
REGULATION OF MOTILIN RELEASE
The effects of bioactive substances and nutrients on the release of
motilin are summarized in Table 2. Cyclic increases of plasma
motilin with 100-min intervals have been reported in fasting
periods in humans, dogs, and opossums (6, 16, 104). This cyclic
increase is inhibited by feeding, and motilin stays low level
during the digestive state. Infusions of nutritional factors such
as glucose and amino acids in the duodenum decrease motilin
release (90), indicating that feeding-related decrease in motilin
release might be caused by sensing digestive nutrients in the
duodenum. However, the effects of fat are controversial: no effect
(90, 96) and stimulatory (95) (Table 2). In humans, feeding
caused a transient increase in plasma motilin concentration, and
both cerebral excitation by feeding and gastric distension by
meals were thought to participate in this motilin increase (103).
Pharmacologically, the cyclic increases of motilin are
inhibited by atropine or hexamethonium, and a vagus nerve
stimulation causes an atropine- or hexamethonium-sensitive
increase in motilin release (105–108). Injection of a muscarinic
agonist, carbachol into the duodenal artery of anesthetized dogs
increased motilin release, and the increase was inhibited by
atropine but not by tetrodotoxin or hexamethonium (106).
Therefore, a neural network involving ganglionic nicotinic
receptors and muscarinic receptors on non-neural tissues could
mediate the motilin release. The muscarinic receptor-mediated
motilin release has been demonstrated in intestinal mucosal
motilin-producing cells of dogs (87).
Stimulation of vagus nerves increased plasma motilin
concentration, but chronic vagotomy and blockade of vagus
nerves by cooling had no effects on motilin release in dogs (93,
95, 109), suggesting that motilin release is regulated by both vagal
and non-vagal cholinergic pathways.
Motilin and erythromycin induce motilin release through
activation of positive feedback mechanism mediated by the 5hydroxytryptamine3 (5-HT 3 ) receptor and nicotinic and
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TABLE 2 | Regulatory stimulants for endogenous motilin release in mammals.
Responses
Bioactive substances
Nutrients
Chemicals
Mechanics
Increase
Decrease
No effect
Acetylcholine [direct action]{dog} (87, 88)
Bombesin [direct action]{dog} (88)
Serotonin [indirect ACh release]{dog} (91, 92)
Motilin [indirect serotonin and ACh release]{dog} (91)
Prostaglandin E2 [indirect ACh release]{dog} (94)
Fat {dog} (95)
Ghrelin {dog} (14)
Somatostatin {dog} (88, 90)
Insulin {dog} (93)
a-adrenerigic receptor {dog} (88)
Pancreatic polypeptide {human} (20)
Feeding {dog} (19)
Glucose {dog} (90)
Amino acid{dog} (90)
Acidification {dog} (100)
CCK [in vitro, in vivo] {dog} (87, 89)
Gastrin [in vivo] {dog} (89)
Secretin [in vitro, in vivo]{dog} (87, 89)
Serotonin [in vitro] {dog} (87)
Alkalinization {dog, suncus} (97–99)
Acidfication {human, dog, pig, suncus} (96, 98, 99, 101, 102)
Increase in luminal pressure {dog} (17)
Gastric distension {human} (103)
Alkalinization {human} (96)
Vagotomy {dog} (93, 95)
contractions through motilin release have been investigated in
Suncus. Mondal et al. (99) examined the association of duodenal
pH and gastric phase III contractions by motilin and reported the
mechanisms for motilin release by a change in duodenal luminal
pH as follows: acidification of the duodenal lumen by gastric acid
stimulates the synthesis of PGE2, which decreases the release of
gastric acid and simultaneously increases 5-HT release from
enteric 5-HT neurons and mucosal enterochromaffin cells; 5-HT
activates the release of bicarbonate from mucosal cells by
activation of the 5-HT4 receptor and the released bicarbonate
increases the luminal pH; finally, alkalinization of the lumen
stimulates the release of motilin to cause the gastric contraction,
although the mechanisms of motilin release by luminal
alkalinization have not been clarified. The interval of
appearance of gastric phase III of the MMC is a required time
that duodenal acidification finally causes alkalinization in the
duodenum through the pathway including PGE2, 5-HT/5-HT4
receptor and bicarbonate. The increase in the 5-HT
concentration in the duodenal lumen by PGE2 is also thought
to contribute to the initiation of duodenal MMC (99).
Takahashi (17) reported another idea of periodic release of
motilin using dogs as model animals. At first, in phase I, gastric,
pancreatic and biliary juices increase luminal pressure of the
duodenum and the increase in pressure stimulates the release of
5-HT from the enterochromaffin cells by mechanoreceptor.
There is a positive circuit between 5-HT release and increase
in luminal pressure. 5-HT stimulates the duodenal pressure and
the pressure increases the release of 5-HT. Duodenal 5-HT
increases duodenal pressure corresponding to intestinal phase
II and III contractions, and the increased duodenal pressure
stimulates the release of motilin. The released motilin further
increases the release of 5-HT, and the increased 5-HT finally
stimulates vagal afferent neurons to cause gastric phase III
through the 5-HT3 receptor on the afferent terminals (115).
Activation of enteric cholinergic neurons by neural MLN-R also
contributes to initiation of the gastric phase III contraction.
Therefore, after appearance of the gastric phase III contraction,
5-HT in enterochromaffin cells is exhausted and it takes times to
refill with 5-HT. This “time” is considered to be the interval of
periodic release of motilin and the motilin-induced gastric phase
III of the MMC. Augmentation of duodenal motility causing an
muscarinic receptors. Motilin stimulates the release of 5hydroxytryptamine (5-HT) and acetylcholine (ACh), and 5-HT
induces ACh release from enteric cholinergic neurons. Finally,
ACh activates muscarinic receptor on the motilin-producing
cells in the duodenum (87, 91, 110).
In dogs, ghrelin decreases motilin release, and cyclic changes
in plasma ghrelin are reversal to cyclic changes in plasma motilin
(A peak of ghrelin is corresponding to bottom of motilin and the
bottom of ghrelin is a peak of motilin). At least in dogs, ghrelin
regulates the release of motilin although the mechanisms of
cyclic changes in ghrelin were not clarified (14). In humans,
however, plasma ghrelin does not fluctuate and does not affect
motilin release (111, 112), suggesting a dog-specific regulation of
motilin release by ghrelin.
Bombesin, prostaglandin E2 (PGE2) and 5-HT stimulate the
release of motilin, but somatostatin, insulin, and noradrenaline
(a-adrenoceptor) decrease (Table 2). Investigation in dispersed
motilin-producing cells in dogs indicated that there are
excitatory muscarinic and bombesin receptors and inhibitory
somatostatin and a-adrenoceptor receptors on the motilinproducing cells (87, 88). Therefore, PGE 2 and 5-HT are
thought to stimulate ACh release from the cholinergic neurons
and to act on the motilin-producing cells indirectly (87, 88, 94).
Duodenal pH influences gastric motility and motilin release.
Dryburgh and Brown (97) reported that duodenal alkalization
increased gastric motor activity in association with increased
motilin concentrations in dogs. Three phasic changes in
duodenal pH (a weak acid period, strong acid period and
alkaline period) observed in dogs were associated with three
types of gastric contractions (the digestive, intermediate, and
interdigestive MMC) (113). An association between duodenal
pH and gastric motility has also been reported in humans.
Woodtli and Owyang (114) found that duodenal pH changed
from 2 to 7.5 during the onset of phase I to phase III, and that pH
was maintained at alkaline from late phase II to phase III of the
gastric MMC. Acidification-induced motilin release was also
observed in the isolated perfused pig duodenum (101). These
studies have indicated that both duodenal acidification and
alkalinization stimulate motilin release and induce GI
contraction like phase III (Table 2). The mechanisms by which
opposite pH stimulations cause almost the same gastric
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Fat {human, dog} (90, 96)
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and intestinal transit (6, 13, 62, 120). The mechanisms for
eliciting rhythmic contractions consisting of contraction and
relaxation are estimated as follows. At the smooth muscle cell
level, MLN-R is coupled with Gq/11 linked to phospholipase C
that synthetizes IP3 and diacylglycerol. IP3 stimulates the release
of Ca2+ from intracellular store and the influx of extracellular Ca2+.
Then increase in intracellular Ca 2+ evokes both muscle
contraction (121, 122), and muscle relaxation through activation
of Ca2+-activated K+-channels (123). On the enteric neuron levels,
it is known that motilin acts on both excitatory cholinergic and
inhibitory nitrergic neurons in the rabbit (124), Suncus (71) and
chicken GI tracts (125). At the vago-vagal reflex level, vagal
efferent neurons innervate both excitatory and inhibitory
neurons in the myenteric plexus.
In the following sections, the effects of motilin on GI motility
in each animal are described in detail.
increase in luminal pressure might be a stimulant for motilin
release (17).
The regulation of motilin release and the corresponding GI
motility have been performed in the dogs, humans and Suncus
(Table 2). Species-related differences including non-mammalian
vertebrates on the regulation of motilin release should be
examined in future.
GI MOTILITY-STIMULATING ACTIONS
IN MAMMALS
The effect of motilin is different depending on animal species, GI
regions and experimental conditions (in vivo and in vitro). In
in vivo experiments, changes in intraluminal pressure, muscle
contractility or muscle myoelectric activity were measured using
conscious or anesthetized animals. Measurements of gastric
emptying and intestinal transit are other ways to evaluate GI
motility. Under these experimental conditions, extrinsic and
intrinsic neural networks of the GI tract are intact, and the
afferent-to-efferent autonomic nervous reflex pathways are also
intact. On the other hand, isolated GI smooth muscle
preparations used in in vitro study are cut off from extrinsic
innervation from brain and sensory innervation connecting to
brain. However, enteric neurons in the myenteric and
submucosal plexuses are intact and functional. These enteric
neurons are able to stimulate electrically. In in vitro experiments,
on the other hand, the local actions of motilin on smooth muscle
cells and enteric neurons can be examined. Based on the results
of functional studies mainly used dogs, rabbits and Suncus, the
mechanisms of GI motility-stimulating actions by motilin are
divided into three pathways (6, 7, 71, 99, 116, 117) (Figure 3):
(i) the action on MLN-Rs located on smooth muscle cells; (ii) the
action on MLN-Rs located on enteric neurons although detailed
neural networks have not been proven, as a result, ACh released
from cholinergic neurons causes contraction through the
muscarinic receptor; and (iii) the activation of the vago-vagal
reflex pathways followed by stimulating vagal efferent neurons
connecting to the enteric neurons. The presence of 5-HT3
receptors has been demonstrated in the terminals of vagus
afferent neurons (115), and motilin-induced contraction in the
vagus-intact stomach, but not in the vagotomized stomach, was
decreased by a 5-HT3 receptor antagonist (94). Thus, motilin is
thought to stimulate the release of 5-HT from enteric neurons
and enterochromaffin cells, and the released 5-HT activates the
5-HT3 receptors on the terminals of vagal afferent neurons.
Contribution of three mechanisms to the motilin-induced GI
contraction is different from animal species and GI regions.
Although expression of MLN-Rs in the CNS has been reported
(5, 23, 118), contribution of motilin and MLN-Rs in the CNS to
the GI motility-stimulating actions might be excluded because
intrathecal or intracerebroventricular injection of motilin failed
to cause GI contraction in dogs (119), and motilin is a
hydrophilic peptide and not able to penetrate the bloodbrain-barrier.
Motilin and erythromycin cause successive phasic phase IIIlike contractions of the GI tract and accelerate gastric emptying
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Dogs
Dogs have been used since the early days of motilin research
because the size is suitable for surgical operations and for
drawing blood samples several times.
Itoh et al. (13) reported that the GI motility patterns of dogs
in the digestive and interdigestive periods are quite different. In
the interdigestive period, i.e., a cyclic increase of GI motility
consisting of phase I, phase II and phase III occurs in the
stomach with an interval of 80-100 min and it propagates to
the caudal direction. Therefore, the cyclic GI motility is called
interdigestive MMC. Motilin caused a contraction similar to that
of MMC in the canine stomach, and this contraction migrated in
the direction toward the small intestine. On the other hand, there
is no MMC in the digestive state, and motilin does not cause any
motility changes in this state (13). In addition, Itoh et al. (19)
demonstrated that the peak of plasma motilin concentration was
associated with the occurrence of phase III activity. Phase III
contraction has been demonstrated to be disrupted by antimotilin serum, or a motilin receptor antagonist (72, 126).
Therefore, motilin has been thought to be an endogenous
regulator of phase III activity of the MMC in the fasting state.
Although Lee et al. (126) showed interruption of the gastric
MMC by treatment with anti-motilin serum, the MMCs in the
distal intestine were resistant, suggesting that the mechanisms of
gastric and intestinal MMCs are different and that motilin is not
a meditator of intestinal MMC.
The mechanisms of motilin-induced contractions in dogs
have been analyzed by autonomic drugs and denervation of
vagus nerves. The motilin-induced gastric contractions were
sensitive to atropine and hexamethonium, indicating the
involvement of a neural pathway including nicotinic and
muscarinic receptors. The involvement of vagus nerves in
motilin-induced contractions has been also reported. A low
dose of motilin stimulated GI motility through activation of
the 5-HT3 receptors on the vagus nerves and vagal reflex
pathway, but a high dose caused an atropine-sensitive GI
contraction through activation of enteric cholinergic nerves
independent of the vagus innervation (127, 128). Therefore, a
physiological concentration of motilin stimulates enteric
neurons both by direct and indirect actions through vagal
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FIGURE 3 | Potential mechanisms of motilin-induced GI motor-stimulating actions. Motilin is synthesized in the M cells of the upper GI tract and is released by
various stimuli, including mechanical, chemical, and biological. The released motilin causes GI motility-stimulating actions through motilin receptors (MLN-Rs) located
on enteric neurons and smooth muscle cells. Neural pathways in the enteric nervous system are complex. Motilin stimulates neural pathways including cholinergic
nicotinic receptors (black), adrenergic receptors, serotonin (5-HT) receptors and NO neurons, and finally acetylcholine (ACh, blue triangle) released from cholinergic
neurons (blue) acts on muscarinic receptors (Mus-R) on smooth muscle cells to cause contraction of stomach and upper intestine. Results of experiments in
conscious animals (dogs, humans and Suncus) indicate that motilin stimulates the release of 5-HT from enteric serotonergic neurons (green) and 5-HT (green
triangle) activates both enteric cholinergic neurons and the vago-vagal reflex pathway through activation of the 5-HT3 receptors on enteric neurons and afferent vagal
terminals. The stimulation of vagus efferent neurons activates neurons in the myenteric plexus to cause contraction of stomach. Since MLN-R is also present in the
intestinal mucosa, it is possible that motilin acts on enterochromaffin cells (EC cells) to release 5-HT. The 5-HT originating from EC cells could also act on enteric
neurons and the vagus afferent terminals. The contribution of these mechanisms might be different depending on the species, regions, and experimental conditions.
The vago-vagal reflex pathway has been demonstrated mainly in the stomach but not in the small intestine. The MLN-R is also expressed in the CNS, but its
functional roles in stimulating GI motility is unknown.
to detect specific motilin binding sites (60). Therefore, the
isolated canine duodenum is insensitive to motilin due to the
lack of MLN-Rs.
However, another in vitro study using the isolated vascularly
perfused canine small intestine showed that intra-arterially
injected motilin increased luminal pressure and that it was
antagonized by tetrodotoxin, atropine and hexamethonium,
indicating that motilin acts on the enteric preganglionic and
postganglionic cholinergic nerves (133). Kellum et al. (134)
showed cholinergically mediated release of 5-HT from enteric
neurons and that the 5-HT3 receptor mediated the contractile
actions of motilin in the canine jejunum. Similar involvement of
5-HT in the motilin-induced contraction was also demonstrated
in the isolated perfused canine stomach. It has been shown that
the neural pathway including a-adrenoceptors is involved in
afferents to vagal efferents pathway. Tanaka et al. (129) reported
that the vagal nerves were not necessary for the initiation or
coordination of fasting gastric MMC patterns but were involved
in the modulation of the contraction pattern during gastric
MMC. Taken together, the results indicate that motilin causes
the phase III of gastric MMC and simultaneously modulates the
frequency and amplitude of the MMC pattern through actions
on the vago-vagal reflex pathway.
In vitro studies using the isolated canine antrum and
duodenum indicated that canine motilin caused contraction at
a very high concentration (130) and that porcine motilin was
ineffective. An approximately 10,000-times higher concentration
of canine motilin was necessary for contraction of the canine
duodenum compared with the concentration for contraction of
the rabbit duodenum (131, 132). A receptor binding study failed
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motilin-induced gastric actions (135). In addition, motilin had
no effect on spontaneous contraction but increased the
amplitude of electrically induced cholinergic contraction in
isolated canine small intestine (136). These observations
indicate that motilin can cause GI contractions via activation
of enteric neurons in in vitro. Immunohistochemical and
molecular biological studies indicated the presence of the
MLN-Rs in the enteric plexus (21).
Taken together, the results in dogs suggest that motilin
stimulates (i) vagal afferent neurons connecting to the vagal
efferent neurons that synapse to enteric neurons through 5-HT/
5-HT3 receptor and (ii) enteric neurons of myenteric plexus
including adrenergic (a-adrenergic receptors), serotonergic (5HT 3 receptors) and cholinergic interneurons (nicotinic
receptor), and that motilin finally releases ACh from
cholinergic neurons, which causes contraction of the stomach,
that is phase III of the MMC, although the arrangement of neural
networks in the myenteric plexus has not been determined
(17) (Figure 3).
Sanger et al. (12) suggested that the motilin system is related
to the ability of vomiting. Application of motilin or erythromycin
frequently caused vomiting in dogs (63, 128). Motilin might be
mimic the vomit-related GI motility (retroperistalsis) in addition
to the regulation of phase III of the MMC in interdigestive
periods. Similar to motilin-induced contraction, 5-HT, the 5HT3 receptor and afferent terminals of the vagus nerves have
been shown to be involved in the vomiting caused by the anticancer drug cisplatin (137). Therefore, the neural pathway
involved in motilin-induced gastric contraction is partially
involved in anti-cancer drug induced vomiting mechanisms.
region, MLN-Rs are predominantly distributed in the neural
fraction in the gastric antrum while those are abundant in the
smooth muscle fraction in the duodenum and colon. Although
the binding affinities for labelled motilin on smooth muscle and
neural binding sites are comparable, the affinities of some
synthetic MLN-R antagonists for neural motilin binding sites
are higher than those for smooth muscle motilin binding sites
(59). Poitras et al. (145) reported that the affinities of motilin and
erythromycin were significantly different in the antral neural
receptor fraction and the duodenal smooth muscle receptor
fraction. However, the details of these differences, i.e., subtypes
of MLN-R, have not been clarified, and only one MLN-R has so
far been cloned in rabbits (76).
There have not been many in vivo studies on GI motility in
rabbits since rabbits eat small meals frequently and their
stomachs will never be empty, i.e., “fasted until death”,
suggesting that rabbits do not have fasting period and
interdigestive GI motility. An in vivo study in which
myoelectric activity of the GI tract was recorded in conscious
rabbits indicated that the migrating myoelectric activity
consisting of three phases originated from the proximal
jejunum, not the stomach and duodenum, being different from
that in dogs, and that the myoelectric activity appears in both
feeding and fasted rabbits at almost the same intervals (146). The
plasma motilin concentration has not been measured in rabbits,
but Guerrero-Lindner et al. (147) examined the effect of motilin
on the GI electric activity. They found that motilin did not affect
the antral electric activity but increased duodenal and jejunum
activities. However, the motilin-induced activity did not
propagate downward and was not followed by a quiescent
period like phase I, being different from the pattern of
spontaneous myoelectric activity, suggesting that motilin is not
likely to be a physiological regulator of the migrating myoelectric
activity in rabbits. Atropine, hexamethonium and ondansetron
did not change the motilin-induced myoelectric activity in
rabbits in contrast to the results in dogs (147), indicating that
motilin acts directly on the smooth muscle MLN-Rs (Figure 3).
However, in ex vivo intestinal preparations (stomach and upper
intestine were isolated together and incubated in an organ bath),
motilin caused migrating motor activity in the duodenum and
these activities were decreased by atropine, indicating that the
motilin-induced actions are of cholinergic neural origin (148).
One of the discrepancies between in vivo and ex vivo studies can
be explained by the concentration of motilin applied
intravenously. In conscious dogs and Suncus, motilin (0.1 µg/
kg, i.v.) was used to initiate phase III-like activity, which was a
neural origin (13, 15), while high concentrations of motilin
(0.6 µg/kg-1.5 µg/kg, 147) used in the rabbits were possible to
act on smooth muscle MLN-Rs and myogenic actions masked
the neural actions. Concerning rabbit myoelectric activity,
Marzio et al. (148) reported the occurrence of a spontaneous
myoelectric complexes originating from the duodenum in an ex
vivo rabbit intestinal preparation, in agreement with the results
of in vivo studies (146, 147). In the ex vivo study, motilin induced
MMCs in both the gastric antrum and duodenum, but
spontaneous myoelectric activities were only elicited in the
Rabbits
Strunz et al. (9, 138) found that the rabbit GI tract was sensitive
to motilin. Considerable GI region-dependent different
responsiveness was found: the upper GI tract including gastric
antrum, duodenum and jejunum was sensitive to motilin, but the
ileum was insensitive (139, 140). In the duodenum, the
contraction induced by motilin was not decreased by atropine
and tetrodotoxin (9, 139, 140) and the responses evoked by
neural stimulation were not modified by motilin (139). These
results suggest a direct action of motilin on smooth muscle. In a
study using a dispersed rabbit antral smooth muscle cells, motilin
caused the shortening of the isolated cells (141). Motilin binding
sites were demonstrated in dispersed muscle cells (142) and in
smooth muscle membrane fractions (143). These results indicate
that MLN-Rs are located on the smooth muscle cell membrane as
myogenic receptors. However, other studies showed
enhancement of neural contractions and stimulation of the
release of [3H]-ACh by motilin, indicating that motilin also
acts on enteric neural MLN-Rs (117, 144). GI regiondependent distributions of myogenic and neural MLN-Rs have
been demonstrated. Poitras et al. (145), Van Assche et al. (143)
and Miller et al. (59) reported the results of [125I]-motilin
binding studies using neural synaptosomes and smooth muscle
membranes obtained from the antrum, duodenum, and colon.
Although both smooth muscle and neural MLN-Rs exist in each
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(11). We also found that an MLN-R-like structure in the guineapig gene database but its homology with human MLN-R was
very low (42.5%), suggesting that functional MLN-R might not
exist in the guinea-pig (11). In the guinea-pig, if the motilin gene
could be expressed and motilin is present in the duodenal
mucosa, the MLN-R gene would be degenerated as in other
rodents (10). Therefore, motilin may not have a GI regulatory
function in the guinea-pigs.
Recording myoelectric activity in conscious guinea-pigs has
indicated that the MMC-like myoelectric activity was elicited in
the duodenum but not in the stomach, and it propagated toward
the jejunum and ileum. These MMCs were not disrupted by
feeding, but the frequency of the complex activity decreased by
feeding (160). The characteristics of the myoelectric complex and
the effects of motilin and ghrelin have not been examined.
duodenum regardless of the absence or presence of motilin in the
organ bath (148). Therefore, although the possibility of
contribution of endogenous motilin to the spontaneous
migrating myoelectric activity in the ex vivo study cannot be
completely excluded, it is suggested that motilin does not initiate
the physiological migrating myoelectric activity in the rabbit
duodenum but possibly regulates the appearance of this activity.
Motilin-induced GI motor-stimulating actions in rabbits have
been also examined under an anesthetized condition. It was
found that motilin caused contractions of the stomach and colon
but not the ileum (140). The high responsiveness of the isolated
colon to motilin (140) and high density of motilin binding sites
(149) found in in vitro studies may reflect the results of the
in vivo study. Mitemcinal, an MLN-R agonist was reported to
increase the defecation in the conscious rabbits (150). Rabbits
belong to the order Lagomorpha, not Rodentia, and are
coprophagous grass-eating animals with a property of hindgut
fermentation. The regulation of colonic motility is important for
rabbits and motilin might be regulator of the colonic motility.
Although rabbits have been widely used in studies for GI
motility-stimulating actions of motilin, the physiological roles
are still not well understood. To determine the roles of motilin in
rabbit GI motility, a study in which measurement of plasma
motilin concentration and an in vivo contraction study using a
physiological dose of motilin are necessary. Since rabbits do not
have an interdigestive GI motility state like that in dogs due to
their eating behavior, motilin might have different roles in
regulation of GI functions including motility, absorption and
secretion. Motilin has been shown to regulate amino acid
absorption in the rabbit intestine (151).
Humans
Similar to the GI motility pattern in dogs, GI motility in humans
can be divided into distinct interdigestive and digestive
contractions. Most of the spontaneous active front of the
MMC in the interdigestive state originates in the stomach (16,
20, 161). Human motilin and the receptor have been identified
(Figure 1 and Table 1). As in dogs, motilin is thought to be the
initiator of phase III of the gastric MMC because exogenous
motilin causes MMC and because the plasma motilin
concentration fluctuates in a cyclic manner in association with
phase III of the MMC originating from the antrum (16, 161,
162). Janssens et al. (20) found that the active fronts of the MMC
originating in the stomach were preceded by a motilin peak and
that pancreatic polypeptide decreased the motilin levels and
active fronts of the gastric MMC without affecting those of the
intestinal MMC. Ondansetron, a 5-HT3 receptor antagonist, also
decreased the cyclic increase of motilin and gastric phase III of
MMC in the stomach, but it did not affect the MMC in the small
intestine (163). Different inhibitory actions of atropine on the
motilin-induced phase III activities in the antral and duodenum
regions also suggest the different mechanisms of motilin-induced
MMC in the stomach and small intestine: phase III activity of
gastric MMC is dependent on muscarinic cholinergic mediation
and the 5-HT3 receptors located on the vagus afferent neurons
but that the contractile action of motilin in the duodenum
involves a non-cholinergic mechanism (164). In addition,
vagotomy abolished the MMC pattern in the stomach but had
a minimal effect on the small intestinal MMC pattern (165).
Therefore, the underlying mechanisms of the gastric MMC and
intestinal MMC in humans are different, and motilin initiates
only the phase III of the gastric MMC through activation of the
5-HT 3 receptors and linked vago-vagal reflex pathway
connecting enteric cholinergic neurons (Figure 3). Unlike in
dogs, ghrelin causes an active front of phase III of the gastric
MMC without changing the plasma motilin concentration in
humans. However, the plasma ghrelin does not fluctuate like
motilin in accordance with the gastric MMC and the role of
ghrelin in regulation of the MMC has not been determined (111,
112). Recently, it was proposed that the MMC signals hunger
sensation from the periphery to the brain in humans (111, 166).
Rodents
It has been known for a long time that motilin does not cause
contraction in non-stimulated and stimulated GI strips of rats
and mice (Mus musculus) in vitro (9, 152) and gastric emptying
in vivo (153).
Recent genome-wide analysis revealed that these mice and
rats are species lacking genes for motilin and its receptor (10, 12).
However, functional studies of recording GI motility indicated
that MMC-like motility occurred at 15 min intervals in the
stomach of fasting rats and mice, and that it was initiated by
ghrelin and inhibited by a ghrelin receptor antagonist, suggesting
that ghrelin, a family of motilin mediated the MMC-like motility
in the rodents (154–156).
In the guinea-pig, however, the possible presence of motilin
mRNA has been reported (52), and other studies indicated that
motilin caused contraction of dispersed GI smooth muscle cells
(157, 158), but isolated GI smooth muscle strips were insensitive
to motilin (9, 11, 159). The discrepancy between the results in
muscle strips and isolated cells might be explained as follows:
motilin simulates both excitatory and inhibitory pathways in
GI strips, and these opposite responses are cancelled and result
in no responses (157). However, the recent re-examination
demonstrated that motilin mRNA was not present and that the
motilin deduced from mRNA (52) did not cause contraction and
did not modify the neural responses in the guinea-pig GI tract
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and canine gastric MMCs. An increase in gastric emptying by
motilin was thought to be due to the gastric motility-stimulating
action of motilin (169, 170). An in vitro study indicated that
motilin preferentially caused contraction of the upper GI tract
depending on the region-dependent distribution of MLN-Rs
(169). Motilin function in rhesus monkeys is thought to be
similar to those in humans, and rhesus monkey would be a
useful animal model for investigating the physiological functions
of motilin in humans.
Therefore, motilin is a hunger hormone transporting a hunger
signal through activation of vagus afferent neurons which also
stimulate the vagus efferent neurons causing gastric phase III.
The in vivo GI motility-stimulating actions of motilin are
similar in humans and dogs, but motilin stimulates contractility
of human GI tract in vitro, in contrast to the isolated canine GI
tract. 13-Nle-motilin caused contraction of the stomach and
small intestine but not large intestine of humans, and atropine
did not decrease the responses (9). Ludtke et al. (167) reported
that the circular muscle strips are more sensitive to motilin than
are longitudinal muscle strips in various regions of the stomach
(pylorus, corpus, fundus, and antrum), and these contractions
were resistant to tetrodotoxin and atropine, but duodenal strips
were insensitive to motilin. These pharmacological studies
indicated the presence of MLN-Rs on smooth muscle cells in a
region-dependent manner. However, the results of a [125I]labeled-motilin binding study in the human stomach showed
the presence of MLN-Rs in both neural synaptosomes and
smooth muscle membranes, and the binding in neural
synaptosomes was dominant (58). As in the rabbit GI tract,
different dissociation constants of MLN-R agonists suggest the
presence of receptor subtypes located on smooth muscle and
enteric neurons (58). However, the presence of MLN-R subtypes
has not been clear at present. Such neural MLN-Rs have been
also demonstrated by an immunohistochemical study, and 5060% of cholinergic neurons were shown to have MLN-R
immunoreactivities (168). A functional study using electrical
field stimulation (EFS) showed enhancement of EFS-induced
cholinergic contraction and increase in smooth muscle tonus by
motilin or MLN-R agonists in the antrum with low activity in the
fundus and small intestine. A high concentration of motilin is
needed to increase smooth muscle tonus through activation of
muscle MLN-Rs (168). Therefore, the results of the in vitro study
clearly indicate the physiological importance of neural MLN-Rs
on gastric cholinergic neurons as suggested by the results of the
in vivo study (164). The neural MLN-Rs on gastric cholinergic
neurons and the 5-HT3 receptors on afferent terminals of the
vagus nerves are responsible for inducing atropine-sensitive
phase III contraction of the MMC in the human stomach
in vivo, whereas the role of myogenic MLN-Rs is not crucial
because of their low affinity and/or low expression level
compared to those of neural MLN-Rs (Figure 3).
House Musk Shrew
In earlier motilin research, dogs (in vivo) and rabbits (in vitro) have
been mainly used. However, these animals are hard to use for
laboratory experiments because of their body sizes and different
responses to motilin from those in humans. From these points of
view, the house musk shrew (Suncus) is very useful. Suncus belongs
to the order of insectivore, and its body size is similar to that of rats,
making it easy to handle in experiments. Interestingly, Suncus has
been used for the development of anti-emetic drugs because it can
vomit differently from the rodents (171). Sanger et al. (12) reported
that the motilin system is correlated with the ability to vomit with
some species exceptions. Suncus motilin and ghrelin (44, 172) and
their receptors (78) have been identified, and functions of motilin in
regulation of GI motility have been investigated in both in vivo and
in vitro (15, 71, 99, 173).
Motilin caused contraction of Suncus gastric strips in an in vitro
study, and the contraction was abolished by atropine and
tetrodotoxin and was significantly decreased by hexamethonium,
phentolamine, ondansetron and naloxone. These results indicate
that the motilin-induced contraction in vitro is mediated by a pure
enteric neural pathway including cholinergic (nicotinic and
muscarinic receptors), adrenergic (a-adrenergic receptor),
serotonergic (5-HT3 receptor) and opiatenergic neurons (opiate
receptor) (71).
The actions of motilin on gastric motility were also observed
in an in vivo study using conscious free-moving Suncus. As in
dogs and humans, the GI motility patterns could be divided into
interdigestive and digestive patterns. During the interdigestive
periods, the stomach and duodenum showed MMCs consisting
of three different phases at intervals of 80-150 min, and the
gastric MMCs propagated to the duodenum. Motilin and
erythromycin caused phase III activity of the gastric MMC
(15). The appearance of phase III activity was inhibited by an
MLN-R antagonist, MA2029 (71).
The contribution of ghrelin to the regulation of the gastric
MMC with motilin has been reported (173). Ghrelin enhances
phase II activity of the MMC in a vagus nerve-dependent
manner, and the duration and amplitude of phase II are
attenuated by vagotomy. Motilin initiated phase III-like activity
in the stomach in a vagus nerve-independent manner, and a
ghrelin receptor antagonist or an MLN-R antagonist decreased
the phase III activity of the gastric MMC. These results indicate
that motilin is involved in the induction of phase III of gastric
MMC as in humans, dogs and that ghrelin is involved in
initiation of phase II and subsequently enhances motilinmediated phase III contractions (173). Motilin mainly activates
the enteric nervous system independently of its actions on vagus
Rhesus Monkey
Rhesus monkeys (Macaca mulatta) have been used in in vivo and
in vitro GI contraction studies to examine the effects of motilininduced responses in comparison with those in humans.
When GI motility was recorded using force transducers, both
interdigestive and digestive contraction patterns were observed
(169). As in humans and dogs, interdigestive MMCs were
observed in both the gastric antrum and duodenum at
intervals of 120-150 min, and exogenous motilin caused the
phase III-like actions of the gastric MMC, and which was
decreased by hexamethonium but not by atropine. Therefore,
motilin activates the neural pathway consisting of intrinsic
cholinergic nerves, but ACh/muscarinic receptor is not a final
mediator of phase III of the MMC, being different from human
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motilin infusion did not induce phase III-like activity and affected
the interval of phase III activity (178). Infusion of acid into the
duodenum increased motilin release, but the increased motilin did
not produce the phase III-like activity (102). Immunoneutralization
of motilin had no effects on appearance of the MMCs (181). Thus, in
pigs, motilin is thought not to be a mediator of the MMCs.
An in vitro study indicated that motilin did not cause
contraction of muscle strips and did not modify neural
responses in the stomach and intestine (182). Little is actually
known about the physiological roles of motilin in porcine GI
function, although motilin was first discovered in pigs.
afferent neurons and smooth muscles, while ghrelin indirectly
regulates phase III activity through its actions on vagus afferent
neurons. Enhancement of phase III activity by ghrelin indicates a
synergistic interaction of motilin and ghrelin in contraction of the
Suncus stomach. Ghrelin decreased the GABAergic nerve-mediated
inhibition in the myenteric plexus that caused enhancement of
motilin-induced gastric phase III contraction (174).
A functional role of the vagus nerves in regulation of the
motilin-induced response and synergistic action of ghrelin have
also been demonstrated in a digestive state. In the vagotomized
Suncus, postprandial irregular contractions were not observed,
indicating the involvement of vagus nerves in the digestive
contractions. In vagus nerve-intact animals, motilin does not
cause contraction in the digestive state but causes contraction in
vagotomized animals, indicating that the vagus nerves play a
suppressive role to the action of motilin (173). However, the
mechanisms have not been clarified yet.
The complicated regulation mechanisms of the gastric MMC
by motilin and ghrelin were indicated for the first time by using
Suncus. Measurements of plasma motilin and ghrelin
concentrations during the gastric MMC might provide more
information about the roles of motilin and involvement of both
peptides in GI motility regulation.
Ruminants
MMCs have been reported in gastric antrum-duodenal regions
of conscious sheep, and the interval between phase III of the
myoelectric complex is approximately 120 min (183). Unlike in
dogs and humans, the myoelectric activity is not changed by
feeding (184). Plasma motilin concentration does not fluctuate
and stays at almost the same level during an appearance of phase
III (185). Infusion of motilin and its receptor agonist,
erythromycin did not cause any changes in myoelectrical
activity of antrum-duodenal regions, although a bolus
application of them increased the myoelectric activity (183).
These findings suggest that motilin is not a mediator of
migrating myoelectric activity in sheep.
Opossum
The opossum (Didelphis virginiana) is a small animal with a
body size similar to that of domestic cats, and it belongs to the
order of Didelphidae. As shown in Figure 1 and Table 1,
opossum motilin and MLN-R have been identified.
GI electric activity has been measured in conscious opossums
and was found to be different in the interdigestive and digestive
periods. In fasted periods, cyclic myoelectric activity complexes
migrating toward the jejunum were observed in the gastric antrum
at 90-min intervals, and it was consisted of three phases as dogs and
humans. They were disrupted by feeding and changed into irregular
small continuous electrical activity (digestive contraction) (175).
The involvement of motilin in the regulation of migrating
myoelectric activity in the opossum was examined. Plasma
motilin concentration changed in a cyclic manner and the
duration between two peaks was about 90 min, and the peak
corresponded to phase III of myoelectric activity in the
duodenum (104). Infusion of motilin (0.3-0.9 µg/kg/h) initiated
phase III activity in the stomach and duodenum, and the activity
propagated toward the jejunum like spontaneous phase III.
Therefore, motilin is proposed to be a mediator of the phase III of
MMC in the stomach or duodenum in the opossum (104).
Summary of Motilin Action in Mammals
The presence of the motilin system and characteristics of MMC/
migrating myoelectrical activity in the stomach and small
intestine, the effects of motilin on GI contractility in in vivo
and in vitro experiments, and changes in the plasma motilin
concentration during the MMC were summarized in Table 3.
Motilin is thought to be a physiological mediator of the phase
III of gastric MMC in humans, dogs, monkeys, Suncus and
opossums, since they eat large meals with a low frequency, and
they have clear fasting and digestive periods. In mammals with
different feeding behaviors (small meals with a high frequency)
such as rabbits, pigs and sheep, physiological roles of motilin in
regulation of the GI motility have not been clearly understood. It
is possible that motilin affects GI motility in the digestive state
because MLN-R agonists, such as ABT-229, EM574 and GM116
increase the gastric emptying in humans, dogs and monkeys
(170, 186–188). However, plasma motilin concentration is
thought to be low in the digestive state and functional roles of
endogenous motilin have not been examined. Motilin transmits a
hunger signal from the periphery to brain in humans (166), and
there might be a relationship among eating style, hunger signals
and functions of motilin in the GI tract of mammals.
Pigs
Motilin was firstly identified in pigs (Sus scrofa domesticus) and
motilin-immunopositive cells were localized in endocrine cells of
the small intestine (1–3, 176).
It was reported that MMC was observed in the duodenum, not in
the stomach, unlike those in dogs and humans (102, 177–180).
However, the myoelectric complexes were not completely disrupted
by feeding (179). An association between plasma motilin
concentration and MMCs was not observed, and plasma motilin
concentration was almost stable during MMCs (177). In addition,
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GI MOTILITY-STIMULATING ACTION IN
NON-MAMMALS
Birds
Isolated GI strips of chickens, quails and pheasants were used in
in vitro contraction studies for motilin (33, 34, 82, 83, 189).
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TABLE 3 | Summary of effects of motilin on gastrointestinal contraction in mammals and birds.
Presence or
absence of
motilin system
Migrating motor (myoelectric)
Migrating motor
complex in fasting period
(myoelectric) complex
[small intestine]
in the fasting period
[stomach]
Disruption
of MMC by
feeding
In vivo study
Human
Presence
Observed
Observed
Yes
Monkey
Presence
Observed
Observed
Yes
Dog
Presence
Observed
Observed
Yes
Suncus
Presence
Observed
Observed
Yes
Rabbit
Presence
Not observed
Observed
No
Opossum
Presence
Observed
Observed
Yes
Not observed
Observed
Observed
Observed
No
Yes
Guinea-pig Absence
Rat
Absence
Mouse
Absence
Observed
Observed
Yes
Pig
Presence
Not observed
Observed
No
Sheep
Presence
Not observed
Observed
No
Chicken
Presence
Not observed
MMC and rhythmic
oscillating complex
(ROCs) (fasting)
No
Induction of gastric
MMC. Increase in
gastric emptying
Induction of gastric
MMC. Increase in
gastric emptying
Induction of gastric
MMC. Increase in
gastric emptying
Induction of gastric
MMC
No effect on jejunum
MMC
Inducton of gastric
MMC.
Not determined
Gastric MMC
mediated by ghrelin
Gastric MMC
mediated by ghrelin
No effect on
duodenal MMC
No effect on
duodenal MMC
No effect on
duodenal MMC.
ROC is produced.
In vitro
study
Plasma motilin
concentration
during MMC or
ROCs
Contraction Cyclic change
Neural and consistent with MMC
myogenic
Myogenic
Not available
contraction
Ineffective
Cyclic change
consistent with MMC
Neural
contraction
Contraction
Neural and
myogenic
Not
available
Ineffective
Ineffective
Not available
Ineffective
Motilin not present
Not available
Cyclic change
consistent with MMC
Motilin not present
Motilin not present
Ineffective
No change during
MMC
Not
No change during
available
MMC
Contraction High level during
Neural and ROCs
myogenic
In in vivo studies, MMC is observed in the chicken GI tract (190–
192) as in mammals. The chicken MMC is consisted of three phases,
basic pattern of quiescence (phase I) and irregular spike activity
(phase II) followed by intense regular spike activity (phase III). The
frequency and duration of chicken MMC are similar with those in
mammals, but the migrating velocity is slow. In addition, the avian
migrating myoelectric activity originates from the duodenum, not
the stomach, and it is not disrupted in the digestive states (190–193).
The detail regulation of the MMCs in chickens has not been
examined, but it is known that the appearance of myoelectric
complex is modulated by some gut hormones including
cholecystokinin and gastrin (191, 192). Rodriguez-Sinovas et al.
(193) reported that motilin was not a mediator of phase III activity
of MMCs in chicken because motilin did not induce phase
III activity.
Rather than MMCs, a new pattern of electric activity called
rhythmic oscillating complexes (ROCs) has been reported in the
chicken small intestine (191, 194). ROCs are highly organized
myoelectric events consisting of several intestinal spike bursts
migrating downward (from the duodenum to ileocecorectal
junction), followed by groups of upward spike bursts from the
end of the small intestine to the gastric pylorus to mix intestinal
luminal contents. It appears only in a fasted condition regardless
of the phase of the myoelectric complex, and they drive the
intestinal contents to the upper part of the GI tract including the
Chicken or human motilin caused contraction of the small
intestine (duodenum, jejunum and ileum) in the three avian
species by activation of MLN-Rs on smooth muscles because
tetrodotoxin or atropine failed to decrease the contraction.
Rabbit duodenum and chicken intestine showed different
contractile activities by human motilin and chicken motilin
(Figure 2), and an MLN-R agonist, erythromycin did not
cause contraction of avian intestine and an MLN-R antagonist,
GM109 also failed to decrease the response of motilin in the
chickens and pheasants, which is strongly suggestive of structural
differences in avian MLN-Rs from mammalian MLN-Rs (33, 34,
82, 83). In fact, the chicken MLN-R has a quite different structure
from those of human and rabbit MLN-Rs (81).
In chickens, quails and pheasants, motilin causes the
strongest contraction in the small intestine followed by the
proventriculus, but does not in the crop, gizzard, and colon
(34, 82, 83, 189). This pattern of different ranking of
responsiveness is common in three avian species. Contraction
in the proventriculus was decreased by tetrodotoxin or atropine,
being different from the response in the small intestine,
suggesting that motilin acts on MLN-Rs located on enteric
cholinergic nerves, which is consistent with the results in
humans and rabbits (58, 145). These region-related different
contraction mechanisms (ileum vs. proventriculus) are also
common in the three avian species (34, 82, 83).
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Action of motilin on GI motility
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frogs, human motilin was ineffective in the upper small intestine of
the Japanese fire belly newt (84). However, our recent study using
the isolated stomach of the fire belly newt indicated that newt
motilin caused a contraction of the gastric strips with high affinity
compared with other motilin peptides (Figure 2C). Furthermore,
small intestinal preparations (upper, middle, and lower intestines)
were insensitive to newt motilin. These results indicate the presence
of the motilin system in the newt which regulates GI motility in a
region-dependent manner as seen in birds and mammals.
stomach and duodenum (191, 194). ROCs have not been
reported in mammals, but ROC-like contractions and
retrograde giant contractions have been observed in mammals
before vomiting (195). Rodriguez-Sinovas et al. (193) reported
that plasma motilin concentration was high during spontaneous
ROCs occurred in the chicken small intestine, and that
exogenous motilin triggered the ROCs activities. This was the
first indication of the involvement of motilin in the regulation of
small intestinal ROCs in birds in the fasting periods.
In in vitro experiments, the responsiveness to motilin was
high in the small intestine including the jejunum and ileum in all
avian species examined (34, 82, 83), and the expression level of
the MLN-R mRNAs was high in the ileum of adult chickens
(196). These observations suggest that the small intestine is the
major target of motilin in birds, and that motilin regulates the
small intestinal contractility in a fasting state.
Teleost Fish
Molecular studies demonstrated the presence of motilin and its
receptor in teleost fish including zebrafish (Danio rerio) (45, 198),
ballan wrasse (Labrus Bergylta) (199), spotted sea bass (Lateolabrax
Maculatus) (8) and other species (Figure 1 and Table 1).
In the intestinal bulb and middle or distal intestinal preparations
of the zebrafish GI tract, human motilin caused a contraction (198).
On the other hand, our study showed that zebrafish motilin caused
only a very small contraction even at high concentrations (over 1
µM), though this peptide activated the zebrafish MLN-R expressed
in HEK293 cells at much lower concentrations (3-100 nM) (86).
The small contraction by zebrafish motilin in vitro would be
responsible for the low expression level of the MLN-Rs, and it is
thought that the motilin system is not a key regulator of intestinal
motility in zebrafish (86). Considerable expression of both motilin
and MLN-R have been demonstrated in the stomach of the ballan
wrasse (199) and the intestine of the spotted sea bass (8), but a GI
contraction study for motilin has not been performed in those fish.
In the spotted sea bass, starvation regulated the expression level of
the motilin gene, and motilin enhanced the mRNA expression of
ghrelin, gastrin, and cholecystokinin (8). These results suggest that
motilin affects the expression of the other gut hormones related to
digestion and energy homeostasis in fish instead of the regulation of
GI motility.
Reptiles
Although motility of isolated GI strips of reptiles (Burmese python)
has been measured (197), the effects of motilin on reptile GI
contractility have not been examined yet despite the molecular
evidence for the presence of motilin and MLN-Rs (Figure 1 and
Table 1). In our study, turtle and alligator motilins caused
contraction of the rabbit duodenum and chicken ileum with low
affinity compared with human motilin or chicken motilin
(Figures 2A, B), indicating that reptile motilins can be agonists
for mammalian and avian MLN-Rs. However, contraction studies
using the GI tract of some reptiles themselves are necessary to
determine that motilin is a regulator of GI contractility in reptiles.
Amphibians
Our recent database searches have indicated the presence of a
motilin-like peptide in newts and axolotl but not in frogs
(Table 1), even though MLN-R is thought to be present both
in newts and frogs (Figure 1).
In in vitro studies using isolated GI tract offrogs, human motilin
caused contraction of stomach of the black-spotted pond frog
(Pelophylax nigromaculatus) and the upper small intestine of the
bullfrog (Lithobates catesbeiana) and tropical clawed frog (Xenopus
tropicalis). However, other GI regions including the middle and
lower intestines were insensitive (84, 85). Therefore, motilin
sensitivity in frogs seems to be dependent on the GI region, as has
been seen in other animals, and the motilin action in the frogs
suggests the possible presence of MLN-R-like receptor. However,
erythromycin or GM109 did not cause contraction or inhibition of
motilin responses in the frog GI tract (85), suggesting that the
structure of MLN-R-like receptor is different from that of
mammals. In a database, an MLN-R candidate was found in the
tropical clawed frog (XM 002935747), and homology of the
Xenopus MLN-R with human MLN-R was relatively low (50%).
Phylogenetic tree analysis of MLN-R clearly showed the different
clade of the Xenopus MLN-R from mammalian MLN-R (Figure 1).
The presence of MLN-R-like receptor might be responsible for
human motilin causing a contraction, but endogenous motilin has
not found in the Xenopus, suggesting that only the motilin gene, but
not the MLN-R gene may have been lost during evolution of anuran
amphibians. In contrast to the results of functional studies in the
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Summary of Motilin Actions in
Non-Mammals
Both motilin and/or MLN-R are present in almost all nonmammalian vertebrates except anuran amphibians (frogs).
Motilin is less effective in causing GI contraction in fish, but it
appears to cause contraction from the amphibian and avian GI
tracts in a region-related manner: the stomach and upper
intestine are sensitive to motilin in amphibian, but the entire
small intestine is highly responsive to motilin in avian species.
Through studies in non-mammals, it can be seen for the first
time that the GI motility-stimulating action of motilin is not
common in vertebrates since motilin stimulates GI contraction
in birds and amphibians but not in fish.
FUNCTIONS OF MOTILIN IN PERIPHERAL
ORGANS OTHER THAN GI TRACT
AND BRAIN
Although the number of studies has been limited, other
biological actions in digestive function and in other organs
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Comparative Study for Motilin Function
been discussed in zebrafish because of high expression of MLN-R
mRNA in the brain (45).
Rats and mice lack motilin system but central and peripheral
actions of motilin have been reported (Table 4). Motilin
stimulates the growth hormone release (203) and feeding (200,
201). Chen et al. (205) reported that motilin caused
depolarization of rat cerebellum Purkinje cells. Increased
neural activity in the amygdala (207) and c-fos expression of
supraoptic nuclei and paraventricular nuclei in the
hypothalamus have been reported (206). Motilin applied to the
CNS decreased bladder contraction (204) and increased gastric
motility in rats (207). In peripheral organs, motilin caused the
vasodilation without changing heart rate in rats (212) and
inhibited proline absorption in the rat jejunum (220). These
motilin responses in rats and mice could be actions on a nonMLN-R that recognizes the sequence of motilin, but the nonMLN-R and its endogenous ligand have not been identified.
including the blood vessels and brain have been reported
(Table 4).
Motilin regulates the exocrine and endocrine functions, and
stimulates the release of gastric acid, pepsinogen, insulin,
somatostatin and pancreatic bicarbonate/protein (213–215,
218, 219). Motilin controls the cyclic release of insulin in
fasted dogs. A comparison of the action of motilin in isolated
islet b-cells and in conscious dogs suggests that motilin
stimulates 5-HT release, and 5-HT activates the vago-vagal
reflex through activation of the 5-HT3 receptors on vagal
afferent terminals, and the vagal efferent stimulates ACh
release, and which activates the muscarinic receptors on islet
b-cells (216, 217). On the other hand, insulin that is released by
glucose after feeding decreases motilin release (93), suggesting
the presence of glucose- and insulin-related negative feedback for
motilin release. In addition, motilin decreases the release of
ghrelin in the dog stomach (14).
In the cardiovascular system, motilin shows increase in blood
flow in dogs (209, 211). MLN-R is dominantly expressed on the
endothelium of gastric artery and the motilin-induced increase
in blood flow is selective for gastric artery. Therefore motilin
regulates both gastric blood flow and motility simultaneously
(211). The endothelial cells-dependent relaxation by motilin was
also reported in the porcine aortic valvular strips (210).
Motilin is thought to act in the CNS because motilinimmunoreactive cells were present in the brains of dogs, pigs
and monkeys (26, 42, 224, 225), and because MLN-R was also
detected in the brains of humans and rabbits (23, 24, 118). But
there are only a few functional studies: Chan-Palay et al. (208)
reported a decrease in neural activity of the lateral vestibular
nucleus by motilin in rabbits; the central actions of motilin have
CONCLUSION
This review summarized the distribution, structure, receptor
expression and function of motilin, with a focus on the GI
motility-stimulatory action of motilin in a range of species
including fish to mammals.
Motilin and MLN-R are present in almost all vertebrates, and
their structures have diversified during evolution. A highly
conserved N-terminal commencing the amino acid indicated
by phenylalanine is thought to be essential for biological activity
in mammalian/avian motilin lineage. Reptile motilin is
considered to be in the transition stage to mammalian/avian
TABLE 4 | Effects of motilin in mammals other than its gastrointestinal motlity-stimulating actions.
Target sites
Effects (animals)
Central nervous system
Increase in food intake (mouse, rat)
Anxiolytic behavior (mouse)
Increase in growth hormone release (rat)
Decrease in urinary bladder contraction (rat, icv)
Depolarization of Purkinje cells (rat)
Increase in c-fos expression of supraoptic nuclei and paraventricular nuclei (rat)
Increase in neural activity of the amyglada (rat)
Decrease in neural activity of the lateral vesitbular nucleus (rabbit)
Relaxation of blood vessels (dog)
Relaxation of aortic valve (pig)
Vasodilation of gastric blood flow (dog)
Vasodilation (rat)
No effects on heart rate (dog)
No effects on heart rate (rat)
Increase in gastric acid release (dog and suncus)
Increase in pepsinogen release (suncus)
Increase in insulin release (dog)
Increase in pancreatic water, bicarbonate and protein release (dog)
Decrease in ghrelin release (dog)
Increase in somatostatin release (dog)
Increase in L-leucine absorption (rabbit)
Decrease in L-proline absorption (rat)
Contraction (dog, human, opposum)
Contraction of lower esophageal sphincter (dog)
Cardiovascular system
Endocrine/Exocrine system
Intestinal mucosa
Gallbladder
Oesophagus
Frontiers in Endocrinology | www.frontiersin.org
References
17
(200, 201)
(202)
(203)
(204)
(205)
(206)
(207)
(208)
(209)
(210)
(211)
(212)
(211)
(212)
(213, 214)
(215)
(216, 217)
(218)
(14)
(219)
(151)
(220)
(104, 221, 222)
(223)
August 2021 | Volume 12 | Article 700884
Kitazawa and Kaiya
Comparative Study for Motilin Function
questions. One is what is the preliminary action of motilin in
fish if it is not GI motility? The distribution of the receptors may
hold the answer to this question. Secondly, if the primary
function was not related to GI motility, why did it come to
regulate GI motility? Finally, why is expression of the motilin
gene lost in anuran amphibians whereas expression of the
receptor remains? This brings the question as to whether this
receptor retains some biological function in vivo. By crossspecies comparisons, it is envisaged that further understanding
and answers to these queries may be addressed.
type, whereas the sequences of fish and amphibian motilins differ
significantly. In the molecular evolution of motilin, there may
have been a major event at the time the reptiles emerged. The
differences in motilin sequences are due to mutations in protein
coding domains during species evolution which were probably
motivated by adaption. The C-terminal sequence is more
conserved than that of the N-terminal, suggesting that the
C-terminal may exert an as yet unknown function in addition
to stimulation of GI motility as mediated via the N-terminal.
GI motility stimulation in a region-specific manner is the
main action of motilin, and motilin is the predominant mediator
of the phase III interdigestive MMC at least in humans, dogs,
monkeys, opossum and Suncus. MLN-Rs mediating GI
contraction located on both smooth muscle cells and on
enteric neurons, and 5-HT released by motilin activates the
vago-vagal reflex pathways. Contribution of these pathways
diversified from species to species, even in mammals, and it is
thought to reflect the evolution of animals and their feeding
behavior. Motilin doesn’t seem to regulate GI motility in fish, but
has acquired a GI motility regulatory function in urodele
amphibians, and that function would have been passed down
to birds and mammals.
It is interesting to anticipate the changes of motilin actions
with consideration of vertebrate evolution. There are three
AUTHOR CONTRIBUTIONS
All authors contributed to the article and approved the
submitted version.
FUNDING
This study was partly supported by JSPS-Japan KAKENHI Grant
number 23570081 and 26440169 to TK and Grant number
26440174 to HK and by Grants-in-Aid to Cooperative
Research from Rakuno Gakuen University 2014 (2014–14).
11. Kitazawa T, Harada R, Sakata I, Sakai T, Kaiya H. A Verification Study of
Gastrointestinal Motility-Stimulating Action of Guinea-Pig Motilin Using
Isolated Gastrointestinal Strips From Rabbits and Guinea-Pigs. Gen Comp
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
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