Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [1-9].

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* Key recommended reading is highlighted with an asterisk

* Alqinyah M, Hooks SB. (2018) Regulating the regulators: Epigenetic, transcriptional, and post-translational regulation of RGS proteins. Cell Signal, 42: 77-87. [PMID:29042285]

* Fuentes N, McCullough M, Panettieri Jr RA, Druey KM. (2021) RGS proteins, GRKs, and beta-arrestins modulate G protein-mediated signaling pathways in asthma. Pharmacol Ther, 223: 107818. [PMID:33600853]

Hollinger S, Hepler JR. (2002) Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol Rev, 54 (3): 527-59. [PMID:12223533]

* Neubig RR, Siderovski DP. (2002) Regulators of G-protein signalling as new central nervous system drug targets. Nat Rev Drug Discov, 1 (3): 187-97. [PMID:12120503]

Ross EM, Wilkie TM. (2000) GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem, 69: 795-827. [PMID:10966476]

* Sethakorn N, Yau DM, Dulin NO. (2010) Non-canonical functions of RGS proteins. Cell Signal, 22 (9): 1274-81. [PMID:20363320]

* Sjögren B. (2017) The evolution of regulators of G protein signalling proteins as drug targets - 20 years in the making: IUPHAR Review 21. Br J Pharmacol, 174 (6): 427-437. [PMID:28098342]

* Sjögren B, Neubig RR. (2010) Thinking outside of the "RGS box": new approaches to therapeutic targeting of regulators of G protein signaling. Mol Pharmacol, 78 (4): 550-7. [PMID:20664002]

Turner EM, Blazer LL, Neubig RR, Husbands SM. (2012) Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins. ACS Med Chem Lett, 3 (2): 146-150. [PMID:22368763]

1. Alqinyah M, Hooks SB. (2018) Regulating the regulators: Epigenetic, transcriptional, and post-translational regulation of RGS proteins. Cell Signal, 42: 77-87. [PMID:29042285]

2. Hollinger S, Hepler JR. (2002) Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol Rev, 54 (3): 527-59. [PMID:12223533]

3. Neubig RR, Siderovski DP. (2002) Regulators of G-protein signalling as new central nervous system drug targets. Nat Rev Drug Discov, 1 (3): 187-97. [PMID:12120503]

4. Ross EM, Wilkie TM. (2000) GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem, 69: 795-827. [PMID:10966476]

5. Siderovski DP, Willard FS. (2005) The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits. Int J Biol Sci, 1 (2): 51-66. [PMID:15951850]

6. Sjögren B. (2011) Regulator of G protein signaling proteins as drug targets: current state and future possibilities. Adv Pharmacol, 62: 315-47. [PMID:21907914]

7. Sjögren B, Blazer LL, Neubig RR. (2010) Regulators of G protein signaling proteins as targets for drug discovery. Prog Mol Biol Transl Sci, 91: 81-119. [PMID:20691960]

8. Zhang P, Mende U. (2011) Regulators of G-protein signaling in the heart and their potential as therapeutic targets. Circ Res, 109 (3): 320-33. [PMID:21778436]

9. Zhong H, Neubig RR. (2001) Regulator of G protein signaling proteins: novel multifunctional drug targets. J Pharmacol Exp Ther, 297 (3): 837-45. [PMID:11356902]

Subcommittee members: Benita Sjögren, Ph.D. (Chairperson) Assistant Professor Dept of Medicinal Chemistry and Molecular Pharmacology Purdue University Robert E. Heine Pharmacy Building, Room 224A 575 W. Stadium Mall Drive West Lafayette, IN 47907 USA Kirk M. Druey Molecular Signal Transduction Section Laboratory of Allergic Diseases National Institute of Allergy and Infectious Diseases/National Institutes of Health Bethesda, Md., USA Rory A. Fisher Department of Pharmacology University of Iowa Carver College of Medicine 51 Newton Rd., BSB 2-512 Iowa City, IA 52242, USA John R. Hepler Department of Pharmacology Emory University School of Medicine Atlanta, GA, USA Shelley B. Hooks 338 Pharmacy South 250 West Green Street Department of Pharmaceutical and Biomedical Sciences University of Georgia Athens, GA 30602 USA Kirill Martemyanov Department of Neuroscience The Scripps Research Institute Jupiter, USA David L. Roman Department of Pharmaceutical Sciences and Experimental Therapeutics Division of Medicinal and Natural Products Chemistry University of Iowa College of Pharmacy 115 South Grand Avenue, Iowa City Iowa 52242, USA Thomas M. Wilkie Pharmacology Dept. UT Southwestern Dallas, TX USA

Other contributors: Bandana Chakravarti Postdoctoral Scholar Department of Pharmacology The University of Iowa Carver College of Medicine 2-505 Bowen Science Building Iowa City, Iowa 52242 USA Somayeh Layeghi-Ghalehsoukhteh Department of Basic Science School of Veterinary Medicine Shiraz University Shiraz Iran Zili Luo Department of Pharmacology The University of Iowa Carver College of Medicine 2-512 Bowen Science Building Iowa City, Iowa 52242 USA Osita W. Ogujiofor Pharmacology Dept. UT Southwestern Dallas, TX USA Hoa Phan Thi Nhu Department of Pharmacology & Toxicology Michigan State University B423 Life Science Building 1355 Bogue St East Lansing MI 48824 USA Vincent Shaw Department of Pharmacology & Toxicology Michigan State University B423 Life Science Building 1355 Bogue St East Lansing MI 48824 USA Laurie Sutton Department of Neuroscience The Scripps Research Institute Jupiter, USA Keqiang Xie Department of Neuroscience The Scripps Research Institute Jupiter, USA Qian Zhang Dept of Medicinal Chemistry and Molecular Pharmacology Purdue University Robert E. Heine Pharmacy Building, Room 224A 575 W. Stadium Mall Drive West Lafayette, IN 47907 USA Yalda Zolghadri Department of Basic Science School of Veterinary Medicine Shiraz University Shiraz Iran