G Protein-coupled Receptors

Nearly 2000 G protein-coupled receptors (GPCRs) have been reported since bovine opsin was cloned in 1983 (1) and the b-adrenergic receptor in 1986 (2). They are classified into over 100 subfamilies according to the sequence homology, ligand structure, and receptor function. A substantial degree of amino acid homology is found among members of a particular subfamily, but comparisons between subfamilies show significantly less or no similarity. Mutations have been observed that relate to a wide spectrum of hereditary and somatic disorders and diseases from cancer to infertility. These mutant receptors are incapable of binding ligand or generating normal signals, constitutively generate signals, or are not appropriately expressed on the cell surface. On the other hand, some mutations are beneficial. For example, a mutation in a chemokine (CCR5) receptor, which is a co-receptor for human immunodeficiency virus (HIV), prevents binding of HIV to target cells and consequently prevents HIV viral infection among the majority of homozygotes with this mutation (3). Although the majority of GPCRs mediate signal transduction via G proteins, emerging evidence indicates that some of these receptors are also capable of sending signals via alternative signal molecules, e.g. Jak2 kinase, phospholipase Cg, or protein kinase C. These alternative pathways are an indication of the overall diversity occurring in the GPCR superfamily. Furthermore, there are putative seven transmembrane molecules, which do not appear to be coupled to a G protein. The most striking difference has been observed in the sites and modes of ligand binding and signal generation, which not only manifests the diversity but also indicates the availability of numerous alternative approaches to clinical and industrial applications. In this review, we describe the general structure and ligand interactions of the receptors, and in the following review, Kobilka’s group (4) focuses on the conformational changes during receptor activation.