Adrenergic receptors. Models for the study of receptors coupled to guanine nucleotide regulatory proteins.

Hormones and most drugs initiate their biological actions by interacting with receptor macromolecules in or on cells. Of the receptors which are located in the plasma membranes of cells, many are coupled to specific effector molecules via intermediary coupling proteins. These are termed “G”-proteins, because they bind and hydrolyze the guanine nucleotide, GTP (1). Among the biological agents whose actions are mediated by such pathways are the catecholamines adrenaline and noradrenaline and their many synthetic congeners that are used as therapeutic agents. As with many other hormones and drugs, several distinct types of receptors for catecholamines have been defined, based both on the distinct physiological actions that they subserve and their pharmacological specificity. These include the al-, a,-, PI-, and @,-adrenergic receptor subtypes (2). Moreover, the different receptor subtypes are coupled to distinct effector pathways. Thus, both PIand &adrenergic receptors stimulate the enzyme adenylate cyclase leading to the generation of CAMP. G. is the guanine nucleotide regulatory protein involved in this pathway (1). a,-Adrenergic receptors inhibit the enzyme via the intermediation of Gi (1). a,-Adrenergic receptors may also stimulate a Na’/H’ antiporter (3), but the relevant G-protein involved, if any, is not known. In contrast, a,-adrenergic receptors activate the enzyme phospholipase C, through an as yet poorly characterized G-protein, leading to the generation of second messengers such as diacylglycerol which activates protein kinase C and inositol trisphosphate which mobilizes intracellular stores of calcium (4). Of the many dozens of receptors coupled to guanine nucleotide regulatory proteins more is known about the family of adrenergic receptors than perhaps any of the others. Thus, all of these receptor subtypes have been purified to homogeneity and reconstituted with guanine ucleotide regulatory proteins in phospholipid vesicles (5); their functional regulation by covalent modification has been extensively studied (6); and most recently, the genes and/or cDNAs for three of the four subtypes have been isolated and sequenced (7-12). From these various studies is emerging an ever-sharpening picture of an extremely large gene family. While this family is exemplified by the adrenergic receptors, it appears to include numerous other receptors for a wide variety of hormones, drugs, and neurotransmitters. This gene family also includes the visual “light receptor” rhodopsin, which is coupled via a guanine nucleotide regulatory protein, transducin, to a cGMP phosphodiesterase (13). I t is also possible that other sensory receptors, e.g. odorant receptors, may be part of this group (14). Recently acquired insights into the structure, function, and regulation of such receptors and their implications for understanding the transmembrane signaling pathways of which they are part form the basis for this brief essay.