G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

摘要

The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gα_s signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gα_s signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.%食物摄取和能量存储是通过下丘脑肽"α-黑素细胞刺激激素"(α-MSH)和"Agouti相关蛋白"(AgRP)对"melanocortin-4 receptor"(MC4R,该物质调控驱动进食行为的神经元）的相反作用被相辅相成地控制的。这项研究识别出一个以前人们不知道的机制，α-MSH和AgRP通过该基质调控来自下丘脑"室旁核"(PVN)的神经元的放电活性。α-MSH被发现将MCR4耦合到Kir7.1钾通道上，使后者关闭，并增强VPN的神经放大。AgRP具有相反效应，使Kir7.1通道打开，抑制PVN神经放电。这些机制（它们独立于以前被发现的那些机制）也许可解释能量平衡的黑皮质素信号作用控制所特有的异常性质和更新我们的神经解剖模型。