Albert P R, Tiberi M
Ottawa Health Research Institute, 451 Smyth Road, University of Ottawa, Ottawa, Canada K1H-8M5.
Trends Endocrinol Metab. 2001 Dec;12(10):453-60. doi: 10.1016/s1043-2760(01)00498-2.
Studies of the serotonin (5-HT) receptors have illustrated several important concepts in G-protein-mediated signaling. These concepts include G-protein specificity and cellular specificity of signaling; mechanisms of transactivation; receptor states and constitutive receptor activity; and the structural basis of coupling. The 5-HT1 receptors couple via specific G(i)/G(o) proteins to inhibitory pathways [inhibition of adenylyl cyclase (AC) activity and regulation of ion channels], but also to stimulate phospholipase C, ACII, and the mitogen-activated protein kinase (MAPK) growth-signaling pathway. 5-HT1 receptors initiate novel endocytotic and Ca(2+)-dependent pathways to activate MAPK acutely, but can downregulate MAPK on chronic activation. These pathways are often mediated via distinct G(i)/G(o)-protein subtypes. Desensitization by multiple protein kinases via receptor phosphorylation is pathway selective. Structural determination of 5-HT1 receptor and G-protein domains that mediate G-protein-specific coupling and desensitization could lead to the development of highly selective ligands that directly regulate receptor-G-protein coupling.
对5-羟色胺（5-HT）受体的研究阐明了G蛋白介导信号传导中的几个重要概念。这些概念包括信号传导的G蛋白特异性和细胞特异性；反式激活机制；受体状态和组成型受体活性；以及偶联的结构基础。5-HT1受体通过特定的G(i)/G(o)蛋白与抑制性途径偶联[抑制腺苷酸环化酶（AC）活性和调节离子通道]，但也能刺激磷脂酶C、ACII和丝裂原活化蛋白激酶（MAPK）生长信号通路。5-HT1受体启动新的内吞和Ca(2+)依赖性途径以急性激活MAPK，但在慢性激活时可下调MAPK。这些途径通常通过不同的G(i)/G(o)蛋白亚型介导。多种蛋白激酶通过受体磷酸化进行的脱敏是途径选择性的。介导G蛋白特异性偶联和脱敏的5-HT1受体和G蛋白结构域的确定可能会导致开发出直接调节受体-G蛋白偶联的高选择性配体。
