Chromostatin, a 20-amino acid peptide derived from chromogranin A, inhibits chromaffin cell secretion.

Abstract

Chromogranin A (CGA) is a ubiquitous 48-kDa secretory protein present in adrenal medulla, anterior pituitary, central and peripheral nervous system, endocrine gut, thyroid, parathyroid, and endocrine pancreas. Recently, we have demonstrated that the protein could be a precursor of bioactive peptides capable of modulating catecholamine secretion from cultured adrenal medullary chromaffin cells. Here we cleaved CGA purified from bovine chromaffmn granules with endoproteinase Lys-C, and we isolated and partially sequenced the peptide inhibiting catecholamine secretion from cultured chromaffim cells. A corresponding synthetic peptide composed of the first 20 N-terminal amino acids produced a dose-dependent inhibition in the 10-9 to 10-6 M range (with an ID.5 of 5 nM) of the catecholamine secretion evoked by carbamoylcholine or by potassium at a depolarizing concentration. This peptide affected secretagogue-induced calcium fluxes but did not alter sodium fluxes. It was found to increase desensitization of cell responses and to modify the kinetics of catecholamine release. Our results indicate that the peptide is extracellularly generated from CGA by a calcium-dependent proteolytic mechanism. We suggest that this peptide, named chromostatin, may be an endocrine modulator of catecholamine-associated responses.

Beta cell chromogranin B is partially segregated in distinct granules and can be released separately from insulin in response to stimulation

“…Based on intracellular distribution studies [7,8] and on data obtained in other cell lines (AtT20 and PC12), these granins are believed to play important roles both in the sorting, packaging and processing of secretion products [11][12][13][14], and in the storage of Ca 2+ within SG lumina [15]. Moreover chromogranin A and/or peptides derived from its processing have been reported to play autocrine, paracrine and endocrine functions upon discharge [16][17][18][19], while CgB has been shown to induce an autocrine inhibition of insulin release from beta cells [20]. However, the functional significance of the latter process in the intact animal remains unclear.…”

Regulatory Effects of Estrogens on the Pituitary Content of Secretogranin II and Chromogranin A

“…Their function is still largely unknown though their participation in intracellular processes such as sorting or packaging of hormones (4) as well as in extracellular regulatory mechanisms on target cells ( 5 ) has been suggested and reported (6,7). Any review concerning these proteins states that secretogranin I1 is highly abundant in the pituitary where it was first discovered, while the level of chromogranin A is lower.…”

Chromogranin A: current status as a precursor for bioactive peptides and a granulogenic/sorting factor in the regulated secretory pathway

“…A tryptic digest of chromaffin granule soluble extract yielded a biological activity that inhibited secretagogue-stimulated catecholamine release from the adrenal medulla [130]. Upon purification of the material, a fraction containing the sequence shown here for bovine chromostatin was obtained, sequenced, and shown to have activity as a synthetic peptide [152]. However, this material was shown to be contaminated by low molecular-weight, non-peptide material which was responsible for its biological activity [153].…”