Review
Partial agonists and G protein-coupled receptor desensitization

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Abstract

Weak or partial agonists induce less desensitization of G protein-coupled receptors (GPCRs) than do strong agonists. However, there have been few attempts to relate partial agonism quantitatively with the various parameters of agonist-induced desensitization, and to elucidate the mechanisms involved. Our understanding of how the treatment of cells and tissues with partial agonists affects their capacity to activate receptors is based on continued progress in defining partial agonism and the mechanisms of desensitization in which protein kinases, phosphatases, endocytosis and recycling play various roles. In this review, current research concerning partial-agonist-induced desensitization of GPCRs and the nature of partial agonism is summarized, and an attempt is made to put the existing knowledge into a working hypothesis concerning the mechanisms that account for the reduced desensitization in response to partial agonists.

Section snippets

Definition of coupling efficiency and comparison to intrinsic efficacy

A number of methods for defining the relative strength of agonists have evolved, notably that developed by Furchgott9 in which the term intrinsic efficacy was proposed to explain the different strengths of agonists. Recently, quantitative formulations were developed by Whaley et al.10, 11 based on the widely accepted Cassel and Selinger12 and Tolkovsky and Levitzki13 models for β2-adrenoceptor activation of Gs-adenylate cyclase. In this model, the relative strengths of agonists were defined as

Mechanisms involved in the rapid phase of agonist-induced GPCR desensitization

It is likely that rapid agonist-induced desensitization of GPCRs will differ between various systems. However, published data suggest that most GPCRs use analogous mechanisms at the receptor level: regulation by second-messenger feedback downstream of their respective G protein–effector interactions, high-occupancy receptor regulation of GRKs coupled with arrestin binding, and endocytosis22, 26, 27. Although the roles of second-messenger-activated protein kinases and GRKs/arrestins will, of

PKA and GRK phosphorylation of the β2-adrenoceptor

Because the β2-adrenoceptor has been the most intensely studied GPCR vis à vis desensitization, it is useful to consider its desensitization in some detail. The response of the β2-adrenoceptor to high occupancy by a strong agonist involves at least the following: PKA-mediated receptor phosphorylation in response to elevated cAMP levels, GRK-mediated receptor phosphorylation, β-arrestin binding to receptor, and receptor endocytosis and recycling. Phosphorylation by PKA of the third intracellular

Correlation of agonist coupling efficiency and desensitization for GPCRs

Although early studies52, 53, 54, 55 established the notion that partial agonists cause less desensitization, more recently the mechanistic basis for the reduced desensitization associated with partial agonist stimulation of intact cells has been explored with a variety of GPCRs, and these studies are reviewed below.

Concluding remarks

Considerable work is needed before we understand the behaviour of partial agonists in the desensitization of GPCRs. Nonetheless, the most complete studies of partial agonists suggest that coupling efficiency (intrinsic efficacy) strongly correlates with the rate of GRK-mediated phosphorylation. To the extent that overall rates of desensitization and endocytosis are determined by the rate of phosphorylation by GRK (and probably binding of arrestin), measurement of coupling efficiencies to G

Chemical name

CGP12177: (−)-4-(3-tert-butylamino-2-hydroxypropoxy)-benzimidazol-2-one

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