Receptor signaling and structure: insights from serotonin-1 receptors.
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.
Albert
P R
PR
Ottawa Health Research Institute, 451 Smyth Road, University of Ottawa, Ottawa, Canada K1H-8M5. palbert@uottawa.ca
Tiberi
M
M
D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology*
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins