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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.

Abstract

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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Acknowledgements

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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DATABASES

FlyBase

Dishevelled

Frizzled

Wnt

 InterPro

DEP domain

GoLoco motif

PDZ domain

PTB domain

Ras-binding domain

RGS domain

 LocusLink

adenylyl cyclase

α2A-adrenoceptor

AT1A angtiotensin receptor

APC

arrestin

axil

axin

calmodulin

CXCR2

dopamine D2 receptor

dopamine D4 receptor

G11α

G12α

G13α

G14α

5

Giα1

Goα

Gqα

Gsα

Gtα

Gzα

GABAB receptor

GAIP

GIRK channels

GRK5

GRK6

GRK7

GSK3β

5-HT receptors

5-HT2A receptor

interleukin-8

LARG

M1 muscarinic acetylcholine receptor

M3 muscarinic acetylcholine receptor

M5 muscarinic acetylcholine receptor

N-type calcium channel

phospholipase C

PLCβ

PLCɛ

RGS1

RGS2

Rgs2

RGS3

RGS4

Rgs4

RGS5

RGS6

RGS7

RGS8

Rgs9

RGS9

RGS10

RGS11

RGS12

RGS13

RGS14

RGS16

RGS17

RGS18

RGS20

RhoA

p115-RhoGEF

PDZ-RhoGEF

SNX13

TNF-α

 Medscape DrugInfo

baclofen

carbachol

clonidine

levadopa

morphine

pilocarpine

 OMIM

Alzheimer's disease

Parkinson's disease

 Saccharomyces Genome Database

Gpa1

SST2

 WormBase

egl-10

FURTHER INFORMATION

 Alliance for Cellular Signalling

Place-preference conditioning

Glossary

Gα-TRANSDUCIN

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

PDZ DOMAIN

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

PLACE-PREFERENCE CONDITIONING:

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

SH2 DOMAIN

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

CHEMORECEPTOR TRIGGERZONE

(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). https://doi.org/10.1038/nrd747

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