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Chromogranin A: a surprising link between granule biogenesis and hypertension
Taeyoon Kim and Y. Peng Loh
Section on Cellular Neurobiology, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
Address correspondence to: Y. Peng Loh, National Institute of Child Health and Human Development, NIH, 49 Convent Drive, Mail Stop Code 4480, Bethesda, Maryland 20892, USA. Phone: (301) 496-3239; Fax: (301) 496-9939; E-mail: lohp@mail.nih.gov.
Find articles by Kim, T. in: JCI | PubMed | Google Scholar
Section on Cellular Neurobiology, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
Address correspondence to: Y. Peng Loh, National Institute of Child Health and Human Development, NIH, 49 Convent Drive, Mail Stop Code 4480, Bethesda, Maryland 20892, USA. Phone: (301) 496-3239; Fax: (301) 496-9939; E-mail: lohp@mail.nih.gov.
Find articles by Loh, Y. in: JCI | PubMed | Google Scholar
Published July 1, 2005 - More info
J Clin Invest. 2005;115(7):1711–1713. https://doi.org/10.1172/JCI25706.
© 2005 The American Society for Clinical Investigation
Chromogranin A (CHGA) was identified as a major soluble protein in adrenal medullary chromaffin granules almost 4 decades ago (1). Since then it has been found to be a ubiquitous protein stored in dense-core secretory granules of the endocrine, exocrine, and nervous systems, along with their respective hormones, enzymes, and neuropeptides and neurotransmitters. CHGA and its derived peptides have been intensely studied with respect to their physiological roles and pathological expression in tumors. CHGA and its processed products have been shown to be involved in the biogenesis of dense-core secretory granules (2), to have a role in immunity against microbes (3), and to function as potential markers for several types of tumors (4). They have also been implicated in neurodegenerative disorders and cardiovascular diseases such as hypertension (4–6). However, these proposed functions of CHGA have not previously been verified in vivo. In this issue of the JCI, Mahapatra et al. (7) used a mouse model with genetic ablation of Chga gene expression to provide the first in vivo evidence to our knowledge for the distinct yet intertwined actions of full-length CHGA and its processed peptide catestatin in the autonomic control of the circulatory system through regulation of chromaffin granule biogenesis and catecholamine release from the adrenal gland.
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CHGA and blood pressure regulation
Primary (genetic or essential) hypertension is complex, as multiple factors derived from cardiovascular, neuronal, renal, and adrenal sources contribute to it. For the last 20 years, a link between CHGA and hypertension has been postulated. Sympathoadrenal activity mediated by catecholamine acts on cardiovascular target cells to increase blood pressure by a so-called “flight or fight” response. After catecholamine is synthesized in the cytoplasm of chromaffin cells, it is transported into dense-core granules via vesicular monoamine transporters. Catecholamine then binds CHGA for storage in the core of the granules (13, 14). Upon stimulation by acetylcholine, catecholamine is cosecreted with CHGA and its derived peptide catestatin from granules in chromaffin cells (Figure 1). Secreted catecholamines in plasma augment blood pressure by activating cardiovascular target cells. Therefore, an increase in blood pressure caused by the action of catecholamine is tightly coupled to the formation of dense-core granules, which is regulated by CHGA. The release of catecholamine is then subsequently blocked by the cosecreted catestatin from chromaffin granules and acts as an antagonist at nicotinic cholinergic receptors, which thus alleviates high blood pressure (Figure 1) (4, 15). The development of hypertension in the Chga KO mice and their subsequent recovery through injection of catestatin or transgenic expression of human Chga clearly demonstrates a role for this peptide in inhibiting blood pressure increases (7). This is consistent with observations that hypertensive patients and subjects with normal blood pressure but with genetic risk of hypertension have decreased catestatin levels compared to those of normotensive controls (16). Interestingly, while catestatin levels were low in these patients, plasma CHGA levels and catecholamine excretion both increased (5, 17). One possible explanation for this result is that there is a processing defect of CHGA in these hypertensive patients. Alternatively, these patients may undergo a pathological upregulation of cholinergic input, which could lead to enhanced exocytosis of chromaffin granules that have not fully matured and secretion of unprocessed CHGA, since processing of CHGA into catestatin takes place in the granules (18). Uninhibited stimulation of chromaffin granule exocytosis with lowered catestatin levels would account for the higher sympathoadrenal activity that leads to increased levels of circulating catecholamine and hypertension in these patients.
Figure 1
Relationship of CHGA-mediated dense-core secretory granule (DCG) biogenesis, catecholamine (CA) secretion, and its subsequent inhibition by the CHGA-derived peptide catestatin in the maintenance of blood pressure by the adrenal gland. CHGA, as a full-length molecule, initiates dense-core secretory granule biogenesis at the trans-Golgi network of adrenal chromaffin cells. Current data suggests that CHGA enhances granule biogenesis by preventing posttranslational degradation of other granule proteins in the Golgi complex. In the cytoplasm, catecholamine is synthesized and transported into the dense-core secretory granules via vesicular monoamine transporters. Upon stimulation by acetylcholine (Ach), catecholamine is coreleased with CHGA and catestatin from the granules. Secreted catecholamine triggers cardiovascular target cells to augment blood flow. This sympathoadrenal activity is then antagonized by the action of catestatin on cholinergic receptors to inhibit catecholamine secretion. [Ca2+]i, intracellular calcium concentration.
In conclusion, the study by Mahapatra et al. (7) describes a mechanism that links the requirement of CHGA for sustained chromaffin granule biogenesis and catecholamine storage to the extracellular inhibition of catecholamine secretion by the CHGA-derived peptide catestatin in the autonomic control of blood pressure in vivo (Figure 1). Their work has several clinical implications. One is the possibility that catestatin may be useful as a therapeutic agent in the treatment of hypertension in humans, although the extent to which the lack of catestatin contributes to human hypertension remains to be determined. Furthermore, screening for polymorphisms in the catestatin domain (19) of the Chga gene in humans could provide insight into the observed genetic predisposition to hypertension.
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