Papers by Enric I. Canela
Journal of Protein Chemistry, 1985
... Enrique I. Canela 1 and Carles M. Nin 1 ... These studies were performed with different metho... more ... Enrique I. Canela 1 and Carles M. Nin 1 ... These studies were performed with different methods, such as amino acid analysis (Bray and Watts, 1966), amperometric determination (Brumby et al., 1965), and spectrophotometric methods (Bergel and Bray, 1959). ...
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Proceedings of the National Academy of Sciences, 2019
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Glia, Aug 19, 2019
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Molecular Neurobiology, Jul 18, 2023
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Research Square (Research Square), Oct 18, 2022
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Springer eBooks, 2023
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Journal of Neurology, Neurosurgery, and Psychiatry, Sep 1, 2014
In the early stages of Huntington’s disease (HD) there is an excess of dopamine production and an... more In the early stages of Huntington’s disease (HD) there is an excess of dopamine production and an over-activation of dopamine D1 receptors (D1R) that can produce not only an imbalance in dopaminergic neurotransmission but can also directly lead to signalling cascades that induce cell death. However, simply blocking of D1R has important drawbacks as it disrupts several physiological functions. Importantly, many of these G-protein coupled receptors (GPCRs) may interact and form the so called heteromers. These receptor complexes confer novel functions and have been proposed as excellent candidates to modulate receptor signalling. Here we propose a new and provocative strategy to reduce the D1R over-activation effects in HD by targeting the recently described receptor complexes of D1R and the histamine receptors H3 (H3R). We show the expression of D1R-H3R heteromers in a HD model of striatal neuronal progenitor cells and in different brain areas of mouse models of HD in the early but not in the late stages of the disease as well as in human control subjects and in grade 2 HD patients but not in grade 3 or 4 HD patients. Upon co-activation of D1R-H3R heteromers, H3R ligands act as a “molecular brake” for D1R signalling. D1R-induced cell death in cells and in brain slices and the signalling cascades responsible for this death are reduced by H3R ligands targeting D1R-H3R heteromers. Chronic treatment of pre-symptomatic HD mice with an H3R antagonist can restore both motor learning and spatial and recognition memory deficits of these animals and inhibits the loss of heteromer expression at more advanced diseases stages. Overall, these results demonstrate that D1R-H3R heteromers play a pivotal role in controlling dopaminergic neurotransmission and indicate that D1R-H3R heteromers can be a new target for treating HD in the pre-symptomatic stages of the disease.
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bioRxiv (Cold Spring Harbor Laboratory), Apr 13, 2019
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Journal of Neuroscience Research, Aug 1, 1990
ABSTRACT
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The Journal of Neuroscience, Mar 5, 2014
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Biology of Sex Differences
Background Memory consolidation is a process required for the formation of long-term memories. Th... more Background Memory consolidation is a process required for the formation of long-term memories. The G-protein-coupled receptor (GPCR) neurokinin-3-receptor (Nk3R) and its interactions with sex hormones seem important for the modulation of fear memory consolidation: Nk3R antagonism in male mice impairs fear memory, but enhances it in females. However, the involvement of the Nk3R as a modulator of other memories in both sexes remains unexplored. Methods We use the novel object recognition paradigm to test the effect of a systemic blockade of Nk3R during memory consolidation. Further, we assess the expression of estrogen receptor α, estrogen receptor β, and androgen receptor and heterodimerization with Nk3R in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) of mice. Results Nk3R systemic antagonism elicited decreased memory consolidation in males while it enhanced it in females during proestrus. Nk3R analysis in the different subregions of the mPFC and the DH showed a hi...
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Pharmacological Research
Polymorphic alleles of the human dopamine D4 receptor gene (DRD4) have been consistently associat... more Polymorphic alleles of the human dopamine D4 receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α2A adrenoceptor (α2AR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D4 receptor (D4R) and α2AR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D4R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α2AR forms functional heteromers with D4R and weather these heteromers show different properties depending on the D4R variant involved. Using cortical brain slices from hD4.7R knock-in and wild-type mice, here, we demonstrate that α2AR and D4R heteromerize and constitute a significant functional population of cortical α2AR and D4R. Moreover, in cortical slices from wild-type mice and in cells transfected with α2AR and D4.4R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD4.7R knock-in mice and in cells expressing the D4.7R polymorphic variant. We also show a lack of efficacy of D4R ligands to promote G protein activation and signaling only within the α2AR-D4.7R heteromer. Taken together, our results suggest that α2AR-D4R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.
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Possible interfaces in A2AR homodimers in complex with Gs. In A–E, the A2AR homodimer was modeled... more Possible interfaces in A2AR homodimers in complex with Gs. In A–E, the A2AR homodimer was modeled through TM4 using the H1-receptor structure as template (A), through TM5 using the structure of squid rhodopsin (B), through TM4/5 using the β1-receptor structure (C), and via TM5/6 (D) and TM1 (E) using the μ-OR structure. TM helices 1, 4, and 5 involved in receptor dimerization are highlighted in dark blue, light blue, and gray, respectively. A2AR protomers bound to Gs (in gray) are shown in light green, whereas Gs-unbound A2AR protomers are shown in dark green. Rluc (blue) is attached to the N-terminal αN helix of Gs, and YFP (yellow) is attached to the C-terminal domain of the Gs-unbound A2AR protomer (light green). It is important to note that the position of YFP is highly dependent on the orientation of the long and highly flexible C-tail of A2AR (102 amino acids, Gln311–Ser412), which was modeled as described for the OXER [32] (see Additional file 9: Figure S9 for details). Despi...
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Graphical description of the stoichiometry of A1R-GFP, A2AR-mCherry or both A1-GFP and A2A-mCherr... more Graphical description of the stoichiometry of A1R-GFP, A2AR-mCherry or both A1-GFP and A2A-mCherry. The fluorescence intensity signal distribution (gray area) detected for more than 7000 independent observations is given for HEK-293T cells expressing A1-GFP (A), A2A-mCherry (D), or both A1-GFP and A2A-mCherry (B, E). The stoichiometry analysis was performed for A1-GFP (A, B) and A2A-mCherry (D, E). Curves approximately delineating the amount of monomers, dimers, trimers, and tetramers are displayed in green for A1-GFP (A, B) and in red for A2A-mCherry (D-E). The occurrence on the cell surface of monomers, dimers, trimers, and tetramers for A1-GFP (C) expressed alone (black bars) or in the presence of A2A-mCherry (blue bars) and for A2A-mCherry (F) expressed alone (black bars) or in the presence of A1-GFP (blue bars) was calculated by stoichiometry analysis from results shown in A, B, D, and E. (TIF 455 kb)
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Molecular dynamics (MD) simulation of the adenosine A1R-A2AR heterotetramer in complex with Gi an... more Molecular dynamics (MD) simulation of the adenosine A1R-A2AR heterotetramer in complex with Gi and Gs. (A) Root-mean-square deviations (rmsd) on protein α-carbons of the whole system (black solid line), of the two A1Rs (orange and red solid lines), of the two A2ARs (light and dark green solid lines), of Gi (gray solid line), and of Gs (gray dotted line) throughout the MD simulation. This color scheme matches with the color of the different proteins depicted in the two adjacent schematic representations. (B) Intermolecular distances between the N-terminal helices of the γ-subunit of Gi and Gs (magenta line), the N-terminal helices of the α-subunit of Gi and Gs (gray line), the N-terminal helix of the α-subunit of Gi and the C-terminal helix (Hx8) of inactive A1R (orange line), the N-terminal helix of the α-subunit of Gs and the C-terminal Hx8 of inactive A2AR (green line), the C-terminal Hx8 of A1R and A2AR (blue lines). These computed intermolecular distances are depicted as double ...
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BRET assays in cells expressing fusion proteins containing hemi-Rluc8 and hemi-Venus moieties fus... more BRET assays in cells expressing fusion proteins containing hemi-Rluc8 and hemi-Venus moieties fused to adenosine receptors or containing the ghrelin GHS1a receptor instead of one of the adenosine receptors. (A) Saturation BRET curve in HEK-293T co-transfected with 1.5 μg of the two cDNAs corresponding to A1R-cRLuc8 and A2AR-nRLuc8 and with increasing amounts of cDNAs corresponding to A1R-nVenus and A2AR-cVenus (equal amounts of the two cDNAs). BRETmax was 35 ± 2 mBU and BRET50 was 16 ± 3 mBU. BRET in cells expressing cRluc8 instead of A1R-cRluc8 gave a linear, non-saturable signal. (B) Comparison of BRET responses using complementary and non-complementary pairs, or replacing one adenosine receptor with the ghrelin GHS1a (gn) receptor. Data are mean ± SD of three different experiments grouped as a function of the amount of BRET acceptor. ***p
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The Journal of Neuroscience, 2021
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Schizophrenia Bulletin, 2020
Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulati... more Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB1R-5-HT2AR heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c). Further, antipsychotic effects on heteromer signaling were tested in vitro in HC/nc and HC/c. Results indicated that heteromer expression was enhanced in both SCZ groups vs HC/nc. Additionally, pooling all 4 groups together, heteromer expression correlated with worse attentional performance and more neurological soft signs (NSS), indicating that these changes may be useful markers for neurocognitive i...
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Early Huntington’s disease (HD) include over-activation of dopamine D1 receptors (D1R), producing... more Early Huntington’s disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD striatal cell model and HD organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD animal models at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits, as well as the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD....
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Papers by Enric I. Canela