Abstract
G protein-coupled receptors (GPCRs) play a major role in signal transduction and are targets of many therapeutic drugs. The regulator of G protein signaling (RGS) proteins form a recently identified protein family, and they strongly modulate the activity of G proteins. Their best known function is to inhibit G protein signaling by accelerating GTP hydrolysis [GTPase activating protein (GAP)] thus turning off G protein signals. RGS proteins also possess non-GAP functions, through both their RGS domains and various non-RGS domains and motifs (e.g., GGL, DEP, DH/PH, PDZ domains and a cysteine string motif). They are a highly diverse protein family, have unique tissue distributions, are strongly regulated by signal transduction events, and will likely play diverse functional roles in living cells. Thus they represent intriguing, novel pharmacological/therapeutic targets. Drugs targeting RGS proteins can be divided into five groups: 1) potentiators of endogenous agonist function, 2) potentiators/desensitization blockers of exogenous GPCR agonists, 3) specificity enhancers of exogenous agonists, 4) antagonists of effector signaling by an RGS protein, and 5) RGS agonists. In addition, a novel subsite distinction within the RGS domain has been proposed with significant functional implications and defined herein as “A-site” and “B-site”. Therefore, RGS proteins should provide exciting new opportunities for drug development.
Footnotes
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Send reprint requests to: Richard R. Neubig, M.D., Ph.D., Department of Pharmacology, 1301 MSRB III/Box 0632, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0632. E-mail:RNeubig{at}umich.edu
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↵1 Many important articles could not be cited in this paper due to the journal's policies limiting the number of references. We apologize to our colleagues whose papers could not be included due to these limitations.
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This work was supported by National Institutes of Health Grant GM 39561.
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↵2 The abbreviation GAP (for GTPase accelerating protein) is used in several ways that may not please grammarians but does facilitate discussion of RGS function. The noun form “GAP” is commonly recognized and understood. A corruption that greatly simplifies speaking or writing about RGS proteins is the verb form “to GAP”, which means to accelerate GTP hydrolysis. Also, it is occasionally used as an adjective as in “GAP activities” or “non-GAP activities” meaning, respectively, functions that do or do not depend on acceleration of GTP hydrolysis.
- Abbreviations:
- GPCR
- G protein-coupled receptor
- RGS
- regulator of G protein signaling
- GAP
- GTPase activating protein
- GIRK
- G protein-coupled inwardly rectifying potassium channel
- GRK
- G protein-coupled receptor kinase
- DEP
- disheveled, egl-10, and pleckstrin
- GGL
- G protein γ-subunit-like
- DH/PH
- Dbl/pleckstrin homology
- GSK3
- glycogen synthase kinase 3
- DIX
- disheveled homology
- PDZ
- PSD-95,disc-large, and ZO-1
- PLC
- phospholipase C
- AKAP
- A-kinase anchoring protein
- IL
- interleukin
- SH
- Src homology
- APC
- adenomatous polyposis coli protein
- PIP3
- phosphatidylinositol 1,4,5-trisphosphate
- GABA
- γ-aminobutyric acid
- Glut
- glucose transporter
- Received September 19, 2000.
- Accepted December 20, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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