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Activation of G Protein-Coupled Receptors: Beyond Two-State Models and Tertiary Conformational Changes.

Park PS, Lodowski DT, Palczewski K

Department of Pharmacology, School of Medicine, CaseWestern Reserve University, Cleveland, Ohio 44106-4965 paul.park@case.edu.

blacksquare, square, filled Abstract Transformation of G protein-coupled receptors (GPCRs) from a quiescent to an active state initiates signal transduction. All GPCRs share a common architecture comprising seven transmembrane-spanning alpha-helices, which accommodates the signal propagation of a diverse repertoire of external stimuli across biological membranes to a heterotrimeric G-protein. Signal propagation through the transmembrane helices likely involves mechanistic features common to all GPCRs. The structure of the light receptor rhodopsin may serve as a prototype for the transmembrane architecture of GPCRs. Early biochemical, biophysical, and pharmacological studies led to the conceptualization of receptor activation based on the context of two-state equilibrium models and conformational changes in protein structure. More recent studies indicate a need to move beyond these classical paradigms and to consider additional aspects of the molecular character of GPCRs, such as the oligomerization and dynamics of the receptor. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 48 is January 6, 2008. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

Published 12 September 2007 in Annu Rev Pharmacol Toxicol.
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