Cellular Signalling Vol. 5, No. 5. pp. 505-518, 1993. 0898-6568/93 $6.00 + .00 Printed in Great Britain. © 1993 Pergamon Press Ltd MINI REVIEW SPECIFICITY OF RECEPTOR--G PROTEIN INTERACTIONS: SEARCHING FOR THE STRUCTURE BEHIND THE SIGNAL KAREN E. HEDIN, KEVIN DUERSONand DAVID E. CLAPHAM* Department of Pharmacology, Mayo Foundation, Guggenheim 7, Rochester, MN 55905, U.S.A. (Received 23 March 1993; and accepted 24 April 1993) 1. INTRODUCTION A LARGEfamily of cell-surface receptors utilize guanine nucleotide-binding, heterotrimeric G proteins for signal transduction [1--4]. At least 100 different receptors of this type have been identified in mammalian tissues by cDNA cloning. Members of this receptor superfamily mediate cellular responses to diverse ligands, including light, odorants, glycoprotein hormones, lipids, alkaloids, peptides and biogenic amines. Intense investigation of the structures and functions of G protein-linked receptors has delineated various intracellular domains required for signal transduction. Nevertheless, it is not yet clear how these struc- tures determine the specificity of hormone responses. Although alternate structures for G protein- linked receptors exist (see below), most of those known consist of single polypeptide chains forming seven putative transmembrane helices through the plasma membrane. The structure of these seven transmembrane-passing receptors (7TM receptors) is based on the electron density map of bacteriorhodopsin, a related protein [5-7]. Figure 1, a schematic of the p2-adrenergic receptor (AR), illustrates how this topology generates at least four intracellular domains: loops I, II and III, and the carboxyi- terminal region (C-tail). We shall refer here to loop III regions approximately 20 residues * Author to whom correspondence should be addressed. from transmembrane domains 5 and 6, as N-III and C-III, respectively. Palmitoylation of a cysteine at position 341 (C-341; single letter amino acid abbreviations will be used through- out) in the fl2-AR C-tail [8], and of two analo- gously placed cysteine residues in rhodopsin [9], generates another intracellular domain, loop IV. A cysteine is conserved at this position in many (but not all) 7TM receptors, suggesting a general functional role for this modification [8]. Binding sites for different ligands occur in the N-terminal region or lie within the trans- membrane helices. 505 Signalling by 7TM receptors When 7TM receptors bind agonists, they catalyse the exchange of GTP for GDP bound by the • subunit of an associated heterotrimeric G protein [10-12]. GTP binding by the ~ sub- unit activates the G protein, promoting its dissociation into ~-GTP and the ]]~ complex. Free forms of both ~-GTP and ]~ directly regulate the activity of effector enzymes. Eventually, the intrinsic GTPase activity of the G protein ~ subunit hydrolyses the GTP and ~-GDP reassociates with ~. The subunit composition of the G protein(s) stimulated by individual 7TM receptors deter- mines the type(s) of signal transduction path- ways triggered by hormone binding [1, 10]. Among the 21 different G protein ~ subunits known to exist [11], only ~s and olfactory- specific gotfsubunits stimulate adenylyi cyclases.