DESENSITIZATION

Desensitization of the G-Protein Coupled Receptors

Desensitization of the G-Protein Coupled Receptors

Introduction

G-protein-coupled receptors (GPCRs) constitute a large and diverse family of proteins whose primary function is to transduce extracellular stimuli into intracellular signals. They are among the largest and most diverse protein families in mammalian genomes. On the basis of homology with rhodopsin, they are predicted to contain seven membrane-spanning helices, an extracellular N-terminus and an intracellular C-terminus. This gives rise to their other names, the 7-TM receptors or the heptahelical receptors. GPCRs transduce extracellular stimuli to give intracellular signals through interaction of their intracellular domains with heterotrimeric G proteins, and the crystal structure of one member of this group, bovine rhodopsin, has recently been solved (Palczewski et al., 2000).

The presence of GPCRs in the genomes of bacteria, yeast, plants, nematodes and other invertebrate groups argues in favor of a relatively early evolutionary origin of this group of molecules. The diversity of GPCRs is dictated both by the multiplicity of stimuli to which they respond, as well as by the variety of intracellular signalling pathways they activate. These include light, neurotransmitters, odorants, biogenic amines, lipids, proteins, amino acids, hormones, nucleotides, chemokines and, undoubtedly, many others. In addition, there are at least 18 different human Ga proteins to which GPCRs can be coupled (Hermans, 2003; Wong, 2003). These Ga proteins form heterotrimeric complexes with Gß subunits, of which there are at least 5 types, and G? subunits, of which there are at least 11 types (Hermans, 2003).

Estimates of the number of GPCRs in the human genome vary widely. Based on their sequences, as well as on their known or suspected functions, there are estimated to be five or six major classes of GPCR. In a recent analysis of the GPCRs in the human genome, more than 800 GPCRs were listed (Fredriksson et al., 2003). Of this total, 701 were in the rhodopsin family (type A) and, of these, 241 were non-olfactory (Fredriksson et al., 2003). According to this analysis, there are approximately 460 type A olfactory receptors, although estimates range from 322 (Glusman et al., 2001; Takeda et al., 2002) to 900 (Venter et al., 2001), of which 347 have already been cloned (Zozulya et al., 2001). This large number of olfactory receptors accounts for the ability of humans to detect a wide variety of exogenous (olfactory) ligands. A study similar to that of Fredriksson et al. (Fredriksson et al., 2003) identified 367 human endoGPCRs and 392 mouse endoGPCRs (Vassilatis et al., 2003); the term endoGPCR refers to GPCRs for endogenous (non-olfactory) ligands. In view of the known existence of alternatively spliced variants and editing isoforms of GPCRs, it is likely that the true number of GPCRs will never be known and is much higher than estimated.

The tree shown illustrates the relationships among the primary protein sequences of 274 type A rhodopsin-like GPCRs; for clarity, the secretin family receptors (of which there are 15), the adhesion receptor family (24), the glutamate receptor family (15) and the frizzled/taste2 receptor family (24) ...