Receptor Mediated G Protein Activation How How Many and Where

INGRID GSANDTNER, CHRISTIAN W. GRUBER, and MICHAEL FREISSMUTH

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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