Trends in Biochemical Sciences
ReviewsAgonist-independent regulation of constitutively active G-protein-coupled receptors
Section snippets
Agonist-independent GPCR activity
Recently, our concepts of GPCRs have been firmly challenged. It is now well established that GPCRs can signal without agonist stimulation. Since the cloning of the gene encoding the hamster β2 adrenergic receptor in 1986 (Ref. [2]), many related genes encoding GPCRs have been cloned (see the GPCRDB database at http://swift.embl-heidelberg.de/7tm/). The availability of this genetic information allowed detailed analysis of (mutant) GPCRs in heterologous expression systems. Spontaneous or
Agonist-independent GPCR activity in human disease
The concept of constitutively active GPCRs has been very useful for understanding the molecular basis of various human disorders[23]. Expression of constitutively active GPCRs [e.g. a CAM α1B, the 5HT2C and the Kaposi-sarcoma-associated herpesvirus (KSHV) GPCR] in vitro can, for example, induce oncogenic cellular transformation24, 25, 26and tumor formation in nude mice24, 27, which indicates the hazardous potential of constitutively active GPCRs. A variety of human diseases—such as retinitis
Constitutive regulation of GPCR activity
Studies on agonist-induced desensitization of the β2 receptor have provided the currently accepted paradigm on the regulation of GPCR function[29]. Agonist exposure leads to a rapid serine/threonine phosphorylation by the family of GPCR kinases (GRK1–GRK6) and/or second-messenger-activated kinases [protein kinase A (PKA) or protein kinase C (PKC)]. Whereas the underlying mechanism(s) of PKA/PKC-mediated GPCR desensitization is still largely unknown, GRK-mediated phosphorylation increases the
Inverse agonists and constitutive GPCR desensitization
Following the effects of inverse agonists on constitutive GPCR signaling, inverse agonists are also expected to interfere with the various mechanisms of GPCR regulation. Inverse agonists inhibit the enhanced basal phosphorylation of a CAM β2 receptor and the wild-type bradykinin B2 receptor30, 41. Consequently, the β2-agonist responsiveness in adenylate cyclase assays was sensitized upon inverse agonist treatment[32]. Similarly, treatment of a CAM α1B or CAM TRH receptor with inverse agonists
Structural instability of GPCRs
Although the opposing effects of inverse agonists and agonists on GPCR expression fit perfectly with the observed opposing effects on second messenger production, additional observations indicate that the regulation of GPCR expression is more complex. Paradoxically, several heterologously expressed CAM GPCRs show GPCR upregulation upon prolonged exposure to agonist. In 3T3F442A cells expressing the CAM Thr373→Lys α2A receptor, prolonged treatment with the agonist UK 14 304 resulted in a
Conclusions
Constitutively active GPCRs are, like agonist-activated GPCRs, spontaneously phosphorylated, desensitized and downregulated. Although it is likely that they are also spontaneously internalized, no actual data are currently available on this topic. The constitutive regulatory processes can be influenced by inverse agonists, although it is clear that the regulation of the expression of CAM GPCRs by receptor-specific ligands is complex. The lack of upregulation by neutral antagonists suggests, for
Acknowledgements
The authors acknowledge support from the EU BIOMED 2 programme `Inverse agonism. Implications for drug design'.
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