G protein-coupled receptors (GPCR) and cellular signaling: a brief history

By Simon A. Hinke, ©2002

The grandparents of modern receptor biology are probably Erhlich and Langley. While Erhlich was not exactly studying what we consider to be receptors in the modern sense, his “side chain theory” attempted to explain how antigens bound to cells. His conclusion was “corpora non agunt nisi fixata” – agents cannot act unless they are bound – a statement frequently quoted in regards to modern receptor biology (Erhlich, 1913). However, contained in Langley’s study of the neuromuscular junction, was the first reference to a “receptive substance” describing the cellular sites of interaction of drugs curare/nicotine and atropine/pilocarpine (Langley, 1909).

The discovery of cyclic AMP and adenylyl cyclase by Sutherland perhaps marks the historical beginning of study of G-protein coupled receptors (Robinson et al., 1967; Hardman et al., 1971). This was followed by proposition of an intermediate transducer to link distinct receptors to a common effector, adenylyl cyclase, and identification of the heterotrimeric G-protein, Gs (Birnbaumer & Rodbell, 1969; Rodbell et al., 1971; Ross & Gilman, 1977). Thus hydrolysis of GTP was found to allow heterotrimeric G-proteins to couple receptors to activation or inhibition of enzymes and ion channels, allowing modulation of cellular physiology by external agents (Cassel & Selinger, 1976; Northup et al., 1980; Codina et al., 1983; Bokoch et al., 1984; Gilman, 1987).

The beta-adrenergic receptor was the first G-protein coupled receptor to be cloned by recombinant DNA technology (Dixon et al., 1986), and thus has been considered to be the prototypical receptor, however, the diversity of the receptors identified has required classification by families and subfamilies, all of which share distinct features. Common to all GPCR are seven alpha-helical transmembrane domains linked by alternating intracellular and extracellular loops, an extracellular amino-terminus, and an intracellular C-terminus.

Extensive study has gone into molecular mechanisms involved in receptor binding, activation and antagonism, and are reviewed elsewhere (Gether & Kobilka, 1998; Horn et al., 1998; Ji et al., 1998; Ulrich et al., 1998; Wess, 1998; Gether, 2000; Gershengorn & Osman, 2001). It is thought that G-protein coupled receptors are the target for approximately 30% of current pharmaceuticals, and with over 2000 members, there are likely even more targets for future drugs (Ji et al., 1998; Gershengorn & Osman, 2001).

References:
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