Novel catecholamine release-inhibitory peptide

交感肾上腺儿茶酚胺的分泌是胞吐的(全有或全无)，不仅释放儿茶酚胺，还释放储存儿茶酚胺的酸性蛋白质：嗜铬颗粒/分泌颗粒，定量的主要成分是嗜铬颗粒A(CHGA)和嗜铬颗粒B(CHGB)。CHGA和CHGB似乎都是必要的因素(开/关？)在儿茶酚胺分泌囊泡的生物发生中。CHGA被切割成生物活性片段，包括内源性形成的儿茶素？抑制儿茶酚胺和囊泡共递质的释放；其特定的抑制机制似乎是烟碱胆碱能拮抗作用。在HL58120的初始阶段收集的数据包括在CHGA和CHGB基因座上发现了实质性和功能性的人类遗传多样性(多态)，包括作为烟碱拮抗剂的3个儿茶素的新变体，以及8个常见的CHGA近端启动子SNPs，这些SNPs导致了常见的CHGA启动子单倍型在嗜铬细胞中具有不同的转录活性。常见的CHGA启动子多态性(尤其是G-988T)预测血浆CHGA浓度。 CHGA(C87T)和CHGB(C85A)中常见的3？-UTR多态预测可遗传 人类双胞胎应激性血压反应的变化。CHGB表达共分离 (LOD=5.84)，在染色体11q24-q25上有一个新的基因位点，这表明存在一个先前未描述的调节人类交感神经流出的主基因。因此，我们将在CHGA上强调常见人类遗传变异(多态)的影响 和CHGB基因座对其生物合成、释放、细胞靶标和自主神经后果的影响。我们将表征儿茶素突变体对烟碱胆碱能受体的抑制作用及其信号转导，以及囊泡共递质的释放。我们将探索CHGA/儿茶素和CHGB基因的多态是否会在体内或体外影响儿茶酚胺的释放和自主神经生理。为了探索这种多态性的意义，我们提出了一系列5个特定的目标，在这些目标中，问题引发了可检验的假设，这些假设可以通过关键的实验来证实或驳斥。这些研究旨在阐明尼古丁受体介导儿茶酚胺释放的遗传调节，以及它们对循环自主控制的后果，从而揭示高血压的遗传风险。

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.