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Regulators of G-Protein signalling as new central nervous system drug targets

Key Points

  • The regulator of G-protein signalling (RGS)-protein family, which has more than 30 members, is an intriguing set of drug targets for central nervous system (CNS) therapeutics.

  • In addition to the conserved RGS-box, they carry a diverse range of other signal-transduction modulatory and scaffolding domains (for example, RhoGEF (Rho guanine-nucleotide-exchange factor), PDZ (PSD95, Dlg and Z0-1/2) and PTB (phosphotyrosine binding) domains).

  • They show differential expression in many brain regions and are dramatically up- or down-regulated by pharmacological stimuli and pathophysiological processes.

  • They strongly modulate G-protein-coupled receptor (GPCR) signalling, and their inhibition should mimic or enhance the action of classical GPCR-agonist drugs.

  • RGS inhibitors could create a new pharmacological class, with properties such as 'specificity enhancement' and 'desensitization reduction', for existing GPCR agonists.


G-protein-coupled receptors (GPCRs) are major targets for drug discovery. The regulator of G-protein signalling (RGS)-protein family has important roles in GPCR signal transduction. RGS proteins contain a conserved RGS-box, which is often accompanied by other signalling regulatory elements. RGS proteins accelerate the deactivation of G proteins to reduce GPCR signalling; however, some also have an effector function and transmit signals. Combining GPCR agonists with RGS inhibitors should potentiate responses, and could markedly increase the agonist's regional specificity. The diversity of RGS proteins with highly localized and dynamically regulated distributions in brain makes them attractive targets for pharmacotherapy of central nervous system disorders.

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Figure 1: Dual role for RGS proteins in GPCR signalling as either inhibitors or effectors.
Figure 2: Surface representations of RGS-boxes that highlight their interaction faces.
Figure 3: Domain architecture of representative members of the nine RGS-protein subfamilies.
Figure 4: RGS–Gα interaction site (the A-site).
Figure 5: Enhancing agonist specificity by RGS inhibition.


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We would like to thank R. Kimple and H. Zhong for assistance with the figures. R.R.N. acknowledges support from the National Institutes of Health. D.P.S. is a Year 2000 Scholar of The EJLB Foundation, a recipient of the Burroughs–Wellcome Fund New Investigator Award in the Basic Pharmacological Sciences, and acknowledges further grant support from the National Institutes of Health.

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 Alliance for Cellular Signalling

Place-preference conditioning



The G protein in the retina that transduces light signals from the photoreceptor GPCR rhodopsin.


(PSD, 95/Dlg and ZO-1/2). Protein–protein interaction domain that binds, in particular, to carboxy-terminal polypeptides.


An often-used behavioural test for the rewarding and/or aversive consequences of drugs by associating these consequences with particular environmental cues.


(Src homology domain 2). A domain that interacts with phosphotyrosine-containing polypeptides.


(CTZ). The 'nausea centre' of the brain, which is located within the brainstem in the area postrema. The CTZ is poorly protected by the blood–brain barrier, and is therefore responsive to blood-borne agents perceived as 'toxins'.

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Neubig, R., Siderovski, D. Regulators of G-Protein signalling as new central nervous system drug targets. Nat Rev Drug Discov 1, 187–197 (2002).

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