Novel catecholamine release-inhibitory peptide

交感肾上腺儿茶酚胺分泌是胞外性的（要么全分泌，要么无分泌），不仅释放儿茶酚胺，还释放储存儿茶酚胺的酸性蛋白：嗜铬颗粒/分泌颗粒，定量主要成分为嗜铬颗粒A （CHGA）和嗜铬颗粒B （CHGB）。CHGA和CHGB似乎都是必要因素(？打开/关闭开关？)在儿茶酚胺分泌囊泡的生物发生过程中。CHGA被切割成具有生物活性的片段，包括内源性形成的睾丸素。抑制儿茶酚胺和囊泡共递质的释放；其特异性抑制机制似乎是烟碱能拮抗。在HL58120的初始阶段收集的数据包括在CHGA和CHGB位点发现了大量和功能性的人类遗传多样性（多态性），包括3个具有不同烟碱拮抗剂效力的catestatin的新变体，以及8个常见的CHGA近端启动子snp，从而在染色质细胞中产生了具有不同转录活性的常见CHGA启动子单倍型。常见CHGA启动子多态性（特别是G-988T）预测血浆CHGA浓度。

Sympathoadrenal catecholamine secretion is exocytotic (all-or-none), releasing not just catecholamines but also the acidic proteins with which catecholamines are stored: chromogranins/secretogranins, quantitatively major components being chromogranin A (CHGA) and chromogranin B (CHGB). Both CHGA and CHGB seem to be necessary factors (?on/off switches?) in the biogenesis of catecholamine secretory vesicles. CHGA is cleaved to biologically active fragments, including the endogenously formed ?catestatin? that inhibits catecholamine and vesicular co-transmitter release; its specific inhibitory mechanism seems to be nicotinic cholinergic antagonism. Data collected in the initial stages of HL58120 include discovery of substantial and functional human genetic diversity (polymorphism) at the CHGA and CHGB loci, including 3 novel variants of catestatin with differential potency as nicotinic antagonists, and 8 common CHGA proximal promoter SNPs, giving rise to common CHGA promoter haplotypes with different transcriptional activities in chromaffin cells. Common CHGA promoter polymorphisms (especially G-988T) predicted plasma CHGA concentration. Common 3?-UTR polymorphisms in both CHGA (C+87T) and CHGB (C+85A) predicted heritable variation in stress blood pressure responses in human twins. CHGB expression cosegregated (LOD=5.84) with a novel locus on chromosome 11q24-q25, suggesting the presence of a previously uncharacterized major gene regulating human sympathetic outflow. We will therefore emphasize effects of common human genetic variation (polymorphism) at the CHGA and CHGB loci on their biosynthesis, release, cellular targets, and autonomic consequences. We will characterize the inhibitory effects of catestatin variants on nicotinic cholinergic receptors and their signal transduction, as well as vesicular co-transmitter release. We will explore whether polymorphisms at CHGA/catestatin and CHGB influence catecholamine release and autonomic physiology in vivo or in vitro. To explore the significance of such polymorphisms, we propose a series of 5 specific aims, in which questions give rise to testable hypotheses that can be confirmed or refuted by crucial experiments. The studies are designed to shed light upon heritable regulation of nicotinic receptor-mediated release of catecholamines, and their consequences for autonomic control of the circulation and hence genetic risk of hypertension.