Receptor signaling and structure: insights from serotonin-1 receptors

被引:56
作者
Albert, PR [1 ]
Tiberi, M [1 ]
机构
[1] Univ Ottawa, Ottawa Hlth Res Inst, Ottawa, ON K1H 8M5, Canada
关键词
D O I
10.1016/S1043-2760(01)00498-2
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 Ca2+-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.
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页码:453 / 460
页数:8
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