Receptor Mediated G Protein Activation How How Many and Where


Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria

For the past 20 years, the G protein cycle has been understood in considerable detail: the G protein cycles between an inactive GDP-bound conformation and an active GTP-bound conformation. By virtue of its guanine nucleotide exchange factor (GEF) activity, the active (agonist--iganded) receptor operates as the switch, which turns on the signal transduction process [1, 2] . The intrinsic GTPase of the G protein a subunit functions as the timed turn-off switch, which is—in most instances—assisted by the GTPase activating protein (GAP) activity of a family of proteins known as regulators of G protein signaling (RGS) proteins [3] . Snapshots exist for these reactions, which allow for extracting several mechanistic details of the underlying reactions at atomic resolution [4]. However, one reaction in this cycle has remained elusive, namely how the receptor- mediated GDP release is brought about. There are three layers, at which this problem has been addressed. These can be referred to as (1) the mechanical problem = receptor-induced movements within the G protein that allow for the formation of a GDP exit path, (2) the dimer problem = the nature of the receptor species that contacts the G protein, and (3) the signalosome problem = anisotropic distribution of receptor-G protein complexes within the membrane and the resulting higher order of organization into signalosomes/signalplexes.

GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions.

Edited by Annette Gilchrist

Copyright © 2010 John Wiley & Sons, Inc.

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