Structure/function relationship of proteins belonging to the family of receptors coupled to GTP‐binding proteins

Abstract

The structural properties of a number of proteins belonging to the family of receptors coupled to GTP binding proteins are discussed in relation to their function.The structure of the ligand binding site and of the regions involved in coupling to the G proteins are analyzed mainly for the adrenergic and muscarinic cholinergic receptors, for which site-directed mutagenesis and chimaeric constructions have been studied. The structure of the genes are compared and the presence of various regulatory elements is discussed in relation to control of expression.Mechanism of desensitization and internalization, while mostly studied for the j2-adrenergic receptor, are proposed to be generally applicable to all G-protein-coupled receptors.A wide variety of membrane receptors for hormones and neurotransmitters are coupled to guanine-nucleotide-binding regulatory 'G' proteins, which upon activation by receptors, stimulate or inhibit various effectors such as enzymes or ion channels. Among the family of receptors coupled to G proteins are those for adrenaline and other catecholamines, the 'adrenergic receptors' and those for acetylcholine and related muscarinic ligands, the 'muscarinic cholinergic' receptors. Other similar proteins belonging to this growing family are those for serotonine, for dopamine, for the tachykinins, and for the pituitary glycoprotein hormones, to mention but a few (Table 1).Several subtypes of these receptors have been defined on the basis of pharmacologic properties and more have been found recently through cloning of homologous genes. Expression of individual receptor subtypes in cells initially devoid of receptors reveal characteristic ligand-binding profiles and activation of different intracellular effector systems. The p1-, j2-and j3-adrenergic, the 5HT-1A serotoninergic (5HT = 5-hydroxytryptamine) and the D1 dopaminergic receptors through activation of a G, (GTP binding stimulatory) protein stimulate the membrane-bound adenylyl cyclase, leading to an increased production of cyclic AMP. The a2A-and a2B- Abbreviations. PAR, /I-adrenergic receptor; E-R7G, family of receptors having seven transmembrane domains, coupled to GTP binding proteins and having an extra long (= 333 residues) extracellular domain; G proteins, GTP binding regulatory proteins (G, = inhibitory, G, = stimulatory, G, = coupled to phospholipase); GRE, glucocorticoid responsive elements; 5HT, 5-hydroxytryptamine; m, muscarinic; R7G, family of receptors having seven transmembrane domains and coupled to GTP binding proteins. adrenergic, the m2 and m4 muscarinic cholinergic, the D2 dopaminergic receptors, through activation of a Gi (GTP binding inhibitory) protein, inhibit this cyclase, whereas the El-adrenergic, the m l , m3 and m5 muscarinic and the 5HT-1C and 5HT-2 serotoninergic receptors through coupling either to a Gi or a Go (GTP binding, coupled to other effectors) protein modulate the hydrolysis of polyphosphoinositol lipids by phospholipase A2 or C leading to the production of two second messengers, inositol tri(tetra)phosp...

Organized Endothelial Cell Surface Signal Transduction in Caveolae Distinct from Glycosylphosphatidylinositol-anchored Protein Microdomains

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Galanin-receptor ligand M40 peptide distinguishes between putative galanin-receptor subtypes.

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Cloned human neuropeptide Y receptor couples to two different second messenger systems.

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