Trends in Pharmacological Sciences
Inverse agonism and the regulation of receptor number
Section snippets
Receptor number regulation
Cellular populations of GPCRs are not static but can be regulated by factors such as the cell cycle and physiological or pathological circumstance. As the primary recognition point for the presence, variation and intensity of hormonal and neurotransmitter-encoded information, their regulation at transcriptional, translational, post-translational and degradative stages is to be anticipated21, 22, 23. One facet of this that has been widely explored is the capacity of agonist ligands to cause
The use of constitutively active mutants
Constitutively active mutant (CAM) GPCRs display enhanced agonist-independent signal transduction compared to the equivalent wild-type GPCR when expressed at similar levels15, 17. This indicates that the CAMs are a closer approximation to an active state conformation of a GPCR than the wild type15, 17. However, as many of the mutants produced display greater maximal output upon addition of agonist than the wild-type receptor (see later, and Appendix A), the mutations are unlikely to represent
The effect of ligand-induced GPCR upregulation
Signalling efficiency may be dependent not only on the level of GPCR expression but also on the levels of expression of G proteins and second messenger-generating enzymes[42]. Thus, changes in signalling resulting from the upregulation of receptors produced by inverse agonists may be dependent upon the cell system used. For example, although sustained treatment of CHO cells expressing a CAM Ī²2-adrenoceptor with the inverse agonist betaxolol results in higher steady-state levels of the receptor
Therapeutic implications
Apart from rare genetic diseases that reflect mutations causing constitutive activity of specific GPCRs, the strong upregulation of some CAM GPCRs in response to inverse agonists is not likely to be relevant to therapeutic situations. Despite this, a number of wild-type GPCRs that display significant levels of constitutive activity such as the Ī²2-adrenoceptor and the H2 receptor and that have been classical targets for clinical intervention via receptor `blocker' strategies have been shown to
Acknowledgements
Acknowledgments
The authors thank the Medical Research Council (UK), the European Community, the American Heart AssociationāTexas Affiliate, the National Institutes of Health and SmithKline Beecham for support of their studies in this area.
References (58)
- et al.
J. Biol. Chem.
(1994) - et al.
J. Biol. Chem.
(1994) - et al.
J. Biol. Chem.
(1996) - et al.
Trends Pharmacol. Sci.
(1995) - et al.
J. Biol. Chem.
(1993) - et al.
J. Biol. Chem.
(1996) - et al.
Trends Pharmacol. Sci.
(1993) - et al.
Trends Neurosci.
(1991) - et al.
Trends Biochem. Sci.
(1992) - et al.
Trends Biochem. Sci.
(1995)