Department of Pharmaceutical Sciences, Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University Barry and Judy Silverman College of Pharmacy, Davie/Fort Lauderdale, FL 33328-2018, USA.
Front Biosci (Landmark Ed). 2024 Oct 14;29(10):355. doi: 10.31083/j.fbl2910355.
The sympathetic nervous system (SNS) consists largely of two different types of components: neurons that release the neurotransmitter norepinephrine (NE, noradrenaline) to modulate homeostasis of the innevrvated effector organ or tissue and adrenal chromaffin cells, which synthesize and secrete the hormone epinephrine (Epi, adrenaline) and some NE into the blood circulation to act at distant organs and tissues that are not directly innervated by the SNS. Like almost every physiological process in the human body, G protein-coupled receptors (GPCRs) tightly modulate both NE release from sympathetic neuronal terminals and catecholamine (CA) secretion from the adrenal medulla. Regulator of G protein Signaling (RGS) proteins, acting as guanosine triphosphatase (GTPase)-activating proteins (GAPs) for the Gα subunits of heterotrimeric guanine nucleotide-binding proteins (G proteins), play a central role in silencing G protein signaling from a plethora of GPCRs. Certain RGS proteins and, in particular, RGS4, have been implicated in regulation of SNS activity and of adrenal chromaffin cell CA secretion. More specifically, recent studies have implicated RGS4 in regulation of NE release from cardiac sympathetic neurons by means of terminating free fatty acid receptor (FFAR)-3 calcium signaling and in regulation of NE and Epi secretion from the adrenal medulla by means of terminating cholinergic calcium signaling in adrenal chromaffin cells. Thus, in this review, we provide an overview of the current literature on the involvement of RGS proteins, with a particular focus on RGS4, in these two processes, i.e., NE release from sympathetic nerve terminals & CA secretion from adrenal chromaffin cells. We also highlight the therapeutic potential of RGS4 pharmacological manipulation for diseases characterized by sympathetic dysfunction or SNS hyperactivity, such as heart failure and hypertension.
交感神经系统（SNS）主要由两种不同类型的成分组成：神经元，释放神经递质去甲肾上腺素（NE，去甲肾上腺素）以调节未受神经支配的效应器或组织的内稳态；以及肾上腺嗜铬细胞，其合成并分泌激素肾上腺素（Epi，肾上腺素）和一些 NE 进入血液循环，作用于远处的器官和组织，这些器官和组织不受 SNS 的直接支配。与人体内几乎所有的生理过程一样，G 蛋白偶联受体（GPCR）紧密调节交感神经末梢的 NE 释放和肾上腺髓质的儿茶酚胺（CA）分泌。G 蛋白信号调节蛋白（RGS）蛋白作为异三聚体鸟苷酸结合蛋白（G 蛋白）的 Gα亚基的鸟苷三磷酸酶（GTPase）-激活蛋白（GAP），在沉默大量 GPCR 的 G 蛋白信号中发挥核心作用。某些 RGS 蛋白，特别是 RGS4，已被牵连到 SNS 活性和肾上腺嗜铬细胞 CA 分泌的调节中。更具体地说，最近的研究表明，RGS4 通过终止游离脂肪酸受体（FFAR）-3 钙信号来调节心脏交感神经元中 NE 的释放，通过终止肾上腺嗜铬细胞中的胆碱能钙信号来调节 NE 和 Epi 的分泌。因此，在这篇综述中，我们提供了关于 RGS 蛋白（特别是 RGS4）参与这两个过程的文献综述，即从交感神经末梢释放 NE 和从肾上腺嗜铬细胞释放 CA。我们还强调了 RGS4 药理学操作的治疗潜力，用于治疗以交感神经功能障碍或 SNS 过度活跃为特征的疾病，如心力衰竭和高血压。
