Novel autocrine feedback control of catecholamine release - A discrete chromogranin A fragment is a noncompetitive nicotinic cholinergic antagonist
Novel autocrine feedback control of catecholamine release - A discrete chromogranin A fragment is a noncompetitive nicotinic cholinergic antagonist
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DOI：
10.1172/jci119686
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发表时间：
1997-09-15
影响因子：
15.9
通讯作者：
Parmer, RJ
中科院分区：
文献类型：
--
作者：
Mahata, SK;OConnor, DT;Parmer, RJ
儿茶酚胺分泌囊泡核心蛋白（嗜铬粒蛋白）含有抑制儿茶酚胺释放的活性，但负责肽的身份一直难以捉摸。大小分级的嗜铬粒蛋白拮抗烟碱胆碱能刺激的儿茶酚胺分泌;抑制剂富含加工的嗜铬粒蛋白片段，并从纯化的嗜铬粒蛋白A中释放出来。在15种合成肽中，涵盖了80%的嗜铬粒蛋白A，其中一种（牛嗜铬粒蛋白A（344 - 364）[RSMRLSFRARGYGFRGPGLQL]或catestatin）是一种有效的、剂量依赖性（IC 50类似于200 nM）、可逆的嗜铬细胞瘤和肾上腺嗜铬细胞以及去甲肾上腺素能神经突分泌抑制剂。针对该肽的抗体阻断了嗜铬粒蛋白A蛋白水解片段对尼古丁刺激的儿茶酚胺分泌的抑制作用。嗜铬粒蛋白A的这一区域在体内嗜铬小泡内被广泛加工。抑制作用是特定的烟碱胆碱能刺激的儿茶酚胺释放，并共享此嗜铬粒蛋白A区从几个物种。烟碱阳离子（Na+，Ca 2+）信号转导被catestatin特异性破坏。甚至高剂量的尼古丁也未能克服这种抑制作用，这表明非竞争性尼古丁拮抗作用。嗜铬粒蛋白A内的这个小结构域可能有助于一种新的自分泌、稳态（负反馈）机制，控制嗜铬细胞和神经元释放儿茶酚胺。
Catecholamine secretory vesicle core proteins (chromogranins) contain an activity that inhibits catecholamine release, but the identity of the responsible peptide has been elusive. Size-fractionated chromogranins antagonized nicotinic cholinergic-stimulated catecholamine secretion; the inhibitor was enriched in processed chromogranin fragments, and was liberated from purified chromogranin A. Of 15 synthetic peptides spanning similar to 80% of chromogranin A, one (bovine chromogranin A(344-364) [RSMRLSFRARGYGFRGPGLQL], or catestatin) was a potent, dose-dependent (IC50 similar to 200 nM), reversible secretory inhibitor on pheochromocytoma and adrenal chromaffin cells, as well as noradrenergic neurites. An antibody directed against this peptide blocked the inhibitory effect of chromogranin A proteolytic fragments on nicotinic-stimulated catecholamine secretion. This region of chromogranin A is extensively processed within chromaffin vesicles in vivo. The inhibitory effect was specific for nicotinic cholinergic stimulation of catecholamine release, and was shared by this chromogranin A region from several species. Nicotinic cationic (Na+, Ca2+) signal transduction was specifically disrupted by catestatin. Even high-dose nicotine failed to overcome the inhibition, suggesting noncompetitive nicotinic antagonism. This small domain within chromogranin A may contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release from chromaffin cells and neurons.