Inverse agonism and the regulation of receptor number

doi:10.1016/S0165-6147(97)01139-5

Trends in Pharmacological Sciences

Volume 18, Issue 12, 1 December 1997, Pages 468-474

https://doi.org/10.1016/S0165-6147(97)01139-5 Get rights and content

Abstract

Inverse agonists are ligands that preferentially stabilize inactive conformations of G protein-coupled receptors. In a range of systems, sustained treatment with inverse agonists can produce substantially greater upregulation of receptor levels than antagonists. The use of constitutively active mutant receptors can exaggerate this effect but may also allow agonists and antagonists to mimic the effect by preventing denaturation of the mutant receptor polypeptide. In this review Graeme Milligan and Richard Bond consider the basis for these effects and their therapeutic implications.

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 β₂-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 β₂-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 Association–Texas Affiliate, the National Institutes of Health and SmithKline Beecham for support of their studies in this area.

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Trends in Pharmacological Sciences

Inverse agonism and the regulation of receptor number

Abstract

Section snippets

Receptor number regulation

The use of constitutively active mutants

The effect of ligand-induced GPCR upregulation

Therapeutic implications

Acknowledgements

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