Rethinking receptor-G protein-effector interactions.
Hundreds of different receptors regulate the activity of effector proteins with the assistance of heterotrimeric guanine nucleotide-binding proteins (G proteins). The hypothesis that G protein-coupled receptors (R) govern their effectors (E) indirectly via a shuttling mechanism involving the exchange of heterotrimeric G proteins (G[alpha betagamma]) or parts thereof (G[alpha], G[betagamma]) between ephemeral R-G and G-E complexes has become firmly established. While there is no direct evidence for the cyclical formation and dissociation of these complexes during signalling, experimental changes in second messenger production, GTPase activity, and the binding characteristics of agonists, antagonists, and guanine nucleotides commonly are believed to reflect perturbations in the equilibria between G protein and the other two components. However, a growing body of evidence seems to argue against the shuttling model. The random, transient association of G protein and receptor is largely inconsistent with the binding of agonists to receptors and the allosteric regulation of that binding by guanine nucleotides. Also, the prevailing paradigm does not readily account for receptor-effector coupling specificity, as the promiscuous interaction of most G proteins with both receptors and effectors in vitro is at odds with the general failure of G proteins to be shared among ostensibly congruous signal transduction pathways in vivo. The latter paradox would be obviated by the simultaneous interaction of G protein with both receptor and effector. Indeed, various findings indicate that R-G-E complexes do occur. How and where in the cell such complexes are assembled and disassembled should provide important clues to the true mechanism of G protein-linked transduction.
Chidiac
P
P
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235-9041, USA.
D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*
D011956:Receptors, Cell Surface; D019204:GTP-Binding Proteins