Because GPCR signaling potentiates many important cellular functions, it is essential that the mechanism of activation is initiated and terminated rapidly, specifically, and precisely even when agonist stimulation is continued. This phenomenon of desen-sitization can function both on the GPCR and G protein levels. Rapid termination of GPCR function can occur through receptor phosphorylation mediated by PKA or PKC (protein kinase C). Receptor phosphorylation is a typical example of negative feedback regulation as the GPCR is directly uncoupled from the G proteins. The desensitization can also target other receptors such as in cases where kinase activation of one GPCR leads to the phosphorylation and desensitization of another GPCR. Receptor phosphorylation can also provide the mechanism to specify coupling to a particular G protein. For example, PKA-mediated phosphorylation of the p2 adrenergic receptor resulted in desensitization in relation to Gs in favor of enhanced coupling to Gi.9
G protein-coupled receptor kinases (GRKs) can also mediate desensitization of GPCRs.4 To date, seven GRK genes have been identified; GRK1 is also called rhodopsin kinase. GRK2 is also known as the p-adrenergic receptor kinase. In the case of GRKs, phosphorylation can occur only on activated or agonist-occupied receptors. Another interacting component is arrestin that binds to the receptor and thereby prevents further GPCR and G protein interactions. There are four arrestins of which two are expressed in the retina as visual and cone arrestins.10 The other two, p-arrestin-1 (arrestin-2) and p-arrestin-2 (arrestin-3), are expressed in many tissues.
Other processes that contribute to GPCR desensitization are receptor degradation, which generally occurs in lysosomes,11 and regulation of gene transcription or translation.12 The termination of GPCR activity is, however, rather slow and can take several hours, whereas the events described for receptor phosphorylation require only minutes. The regulation of GPCRs also occurs at a post-expression level. The family of 25 proteins known as regulators of G protein signaling (RGS) serve as GTPase-activating proteins (GAPs) for G proteins.13 The RGSs possess characteristic 130 amino acid homologous regions. The various RGSs seem to have selectivity for specific G proteins and even distinct receptors. The mechanism of RGSs is to enhance the hydrolysis rate of GTP, which should aid in termination of receptor activity. Knockout studies on RGS9 clearly demonstrated that light-activated rhodopsin was deactivated.14
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