Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 97 (22): 12272-12277

Copyright © 2000 by the National Academy of Sciences.


Regulation of T cell activation, anxiety, and male aggression by RGS2

Antonio J. Oliveira-dos-Santos*, Goichi Matsumoto*, Bryan E. Snow*, Donglin Bai{dagger}, Frank P. Houston{ddagger}, Ian Q. Whishaw§, Sanjeev Mariathasan, Takehiko Sasaki*, Andrew Wakeham*, Pamela S. Ohashi, John C. Roder{dagger}, Carol A. Barnes{ddagger}, David P. Siderovski||, and Josef M. Penninger*,**

*Amgen Institute and Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Toronto, ON M5G 2C1 Canada; {dagger}Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5S1A8 Canada; {ddagger}Arizona Research Laboratories, Division of Neural Systems, Memory, and Aging, University of Arizona, Tucson, AZ 85724; §Department of Psychology, University of Lethbridge, AB T1K3 M4 Canada; and ||Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599

Accepted for publication August 29, 2000.

Received for publication June 20, 2000.

Abstract: Regulators of G protein signaling (RGS) proteins accelerate the GTPase activity of Gα protein subunits in vitro, negatively regulating G protein-coupled receptor signaling. The physiological role of mammalian RGS proteins is largely unknown. The RGS family member rgs2 was cloned as an immediate early response gene up-regulated in T lymphocytes after activation. To investigate the role of RGS2 in vivo, we generated rgs2-deficient mice. We show that targeted mutation of rgs2 in mice leads to reduced T cell proliferation and IL-2 production, which translates in an impaired antiviral immunity in vivo. Interestingly, rgs2–/– mice also display increased anxiety responses and decreased male aggression in the absence of cognitive or motor deficits. RGS2 also controls synaptic development and basal electrical activity in hippocampal CA1 neurons. Thus, RGS2 plays an important role in T cell activation, synapse development in the hippocampus, and emotive behaviors.

** To whom reprint requests should be addressed. E-mail: jpenning{at}

Communicated by Alfred G. Gilman, University of Texas Southwestern Medical Center, Dallas, TX

Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.220414397.

Article and publication date are at

Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor-adenylyl cyclase axis.
A. Stewart, B. Maity, A. M. Wunsch, F. Meng, Q. Wu, J. A. Wemmie, and R. A. Fisher (2014)
FASEB J 28, 1735-1744
   Abstract »    Full Text »    PDF »
RGS3 controls T lymphocyte migration in a model of Th2-mediated airway inflammation.
J. W. Williams, D. Yau, N. Sethakorn, J. Kach, E. B. Reed, T. V. Moore, J. Cannon, X. Jin, H. Xing, A. J. Muslin, et al. (2013)
Am J Physiol Lung Cell Mol Physiol 305, L693-L701
   Abstract »    Full Text »    PDF »
Regulator of G Protein Signaling 2 Deficiency Causes Endothelial Dysfunction and Impaired Endothelium-derived Hyperpolarizing Factor-mediated Relaxation by Dysregulating Gi/o Signaling.
P. Osei-Owusu, R. Sabharwal, K. M. Kaltenbronn, M.-H. Rhee, M. W. Chapleau, H. H. Dietrich, and K. J. Blumer (2012)
J. Biol. Chem. 287, 12541-12549
   Abstract »    Full Text »    PDF »
{beta}2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids.
N. S. Holden, M. J. Bell, C. F. Rider, E. M. King, D. D. Gaunt, R. Leigh, M. Johnson, D. P. Siderovski, S. P. Heximer, M. A. Giembycz, et al. (2011)
PNAS 108, 19713-19718
   Abstract »    Full Text »    PDF »
Regulators of G-Protein Signaling and Their G{alpha} Substrates: Promises and Challenges in Their Use as Drug Discovery Targets.
A. J. Kimple, D. E. Bosch, P. M. Giguere, and D. P. Siderovski (2011)
Pharmacol. Rev. 63, 728-749
   Abstract »    Full Text »    PDF »
Renal Actions of RGS2 Control Blood Pressure.
S. B. Gurley, R. C. Griffiths, M. E. Mendelsohn, R. H. Karas, and T. M. Coffman (2010)
J. Am. Soc. Nephrol. 21, 1847-1851
   Abstract »    Full Text »    PDF »
Evidence for enhanced M3 muscarinic receptor function and sensitivity to atrial arrhythmia in the RGS2-deficient mouse.
J. M. Tuomi, P. Chidiac, and D. L. Jones (2010)
Am J Physiol Heart Circ Physiol 298, H554-H561
   Abstract »    Full Text »    PDF »
The Function of Activity-Regulated Genes in the Nervous System.
S. Loebrich and E. Nedivi (2009)
Physiol Rev 89, 1079-1103
   Abstract »    Full Text »    PDF »
Structural Determinants of G-protein {alpha} Subunit Selectivity by Regulator of G-protein Signaling 2 (RGS2).
A. J. Kimple, M. Soundararajan, S. Q. Hutsell, A. K. Roos, D. J. Urban, V. Setola, B. R. S. Temple, B. L. Roth, S. Knapp, F. S. Willard, et al. (2009)
J. Biol. Chem. 284, 19402-19411
   Abstract »    Full Text »    PDF »
Evidence for a Direct and Functional Interaction between the Regulators of G Protein Signaling-2 and Phosphorylated C Terminus of Cholecystokinin-2 Receptor.
I. Langer, I. G. Tikhonova, C. Boulegue, J.-P. Esteve, S. Vatinel, A. Ferrand, L. Moroder, P. Robberecht, and D. Fourmy (2009)
Mol. Pharmacol. 75, 502-513
   Abstract »    Full Text »    PDF »
RGS13 Controls G Protein-Coupled Receptor-Evoked Responses of Human Mast Cells.
G. Bansal, J. A. DiVietro, H. S. Kuehn, S. Rao, K. H. Nocka, A. M. Gilfillan, and K. M. Druey (2008)
J. Immunol. 181, 7882-7890
   Abstract »    Full Text »    PDF »
Structural diversity in the RGS domain and its interaction with heterotrimeric G protein {alpha}-subunits.
M. Soundararajan, F. S. Willard, A. J. Kimple, A. P. Turnbull, L. J. Ball, G. A. Schoch, C. Gileadi, O. Y. Fedorov, E. F. Dowler, V. A. Higman, et al. (2008)
PNAS 105, 6457-6462
   Abstract »    Full Text »    PDF »
Generation and Characterization of rgs5 Mutant Mice.
M. H. Nisancioglu, W. M. Mahoney Jr., D. D. Kimmel, S. M. Schwartz, C. Betsholtz, and G. Genove (2008)
Mol. Cell. Biol. 28, 2324-2331
   Abstract »    Full Text »    PDF »
Increased Renal Responsiveness to Vasopressin and Enhanced V2 Receptor Signaling in RGS2-/- Mice.
A. M. Zuber, D. Singer, J. M. Penninger, B. C. Rossier, and D. Firsov (2007)
J. Am. Soc. Nephrol. 18, 1672-1678
   Abstract »    Full Text »    PDF »
RGS Proteins: Swiss Army Knives in Seven-Transmembrane Domain Receptor Signaling Networks.
S. P. Heximer and K. J. Blumer (2007)
Sci. STKE 2007, pe2
   Abstract »    Full Text »    PDF »
Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts.
A. A. Roy, C. Nunn, H. Ming, M.-X. Zou, J. Penninger, L. A. Kirshenbaum, S. J. Dixon, and P. Chidiac (2006)
J. Biol. Chem. 281, 32684-32693
   Abstract »    Full Text »    PDF »
Endogenous Regulator of G-Protein Signaling Proteins Regulate the Kinetics of G{alpha}q/11-Mediated Modulation of Ion Channels in Central Nervous System Neurons.
M. A. Clark and N. A. Lambert (2006)
Mol. Pharmacol. 69, 1280-1287
   Abstract »    Full Text »    PDF »
Mammalian G Proteins and Their Cell Type Specific Functions.
N. Wettschureck and S. Offermanns (2005)
Physiol Rev 85, 1159-1204
   Abstract »    Full Text »    PDF »
Regulator of G protein signaling (RGS2)-deficient mice: a novel model to study autonomic nervous system function.
H. M. Stauss (2005)
Am J Physiol Regulatory Integrative Comp Physiol 288, R1091-R1092
   Full Text »    PDF »
Autonomic nervous system and blood pressure regulation in RGS2-deficient mice.
V. Gross, J. Tank, M. Obst, R. Plehm, K. J. Blumer, A. Diedrich, J. Jordan, and F. C. Luft (2005)
Am J Physiol Regulatory Integrative Comp Physiol 288, R1134-R1142
   Abstract »    Full Text »    PDF »
RGS2 Is a Mediator of Nitric Oxide Action on Blood Pressure and Vasoconstrictor Signaling.
X. Sun, K. M. Kaltenbronn, T. H. Steinberg, and K. J. Blumer (2005)
Mol. Pharmacol. 67, 631-639
   Abstract »    Full Text »    PDF »
RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation.
J. Schwable, C. Choudhary, C. Thiede, L. Tickenbrock, B. Sargin, C. Steur, M. Rehage, A. Rudat, C. Brandts, W. E. Berdel, et al. (2005)
Blood 105, 2107-2114
   Abstract »    Full Text »    PDF »
Transcriptional Response to Corticotropin-Releasing Factor in AtT-20 Cells.
P. J. Peeters, H. W. Gohlmann, I. Van den Wyngaert, S. M. Swagemakers, L. Bijnens, S. U. Kass, and T. Steckler (2004)
Mol. Pharmacol. 66, 1083-1092
   Abstract »    Full Text »    PDF »
Role of Regulator of G Protein Signaling 2 (RGS2) in Ca2+ Oscillations and Adaptation of Ca2+ Signaling to Reduce Excitability of RGS2-/- Cells.
X. Wang, G. Huang, X. Luo, J. M. Penninger, and S. Muallem (2004)
J. Biol. Chem. 279, 41642-41649
   Abstract »    Full Text »    PDF »
A Functional Polymorphism in RGS6 Modulates the Risk of Bladder Cancer.
D. M. Berman, Y. Wang, Z. Liu, Q. Dong, L.-A. Burke, L. A. Liotta, R. Fisher, and X. Wu (2004)
Cancer Res. 64, 6820-6826
   Abstract »    Full Text »    PDF »
A specific gene expression program triggered by Gram-positive bacteria in the cytosol.
R. L. McCaffrey, P. Fawcett, M. O'Riordan, K.-D. Lee, E. A. Havell, P. O. Brown, and D. A. Portnoy (2004)
PNAS 101, 11386-11391
   Abstract »    Full Text »    PDF »
Role of Regulator of G Protein Signaling 16 in Inflammation- Induced T Lymphocyte Migration and Activation.
E. Lippert, D. L. Yowe, J.-A. Gonzalo, J. P. Justice, J. M. Webster, E. R. Fedyk, M. Hodge, C. Miller, J.-C. Gutierrez-Ramos, F. Borrego, et al. (2003)
J. Immunol. 171, 1542-1555
   Abstract »    Full Text »    PDF »
Gene Array and Protein Expression Profiles Suggest Post-transcriptional Regulation during CD8+ T Cell Differentiation.
C. M. Cham, H. Xu, J. P. O'Keefe, F. V. Rivas, P. Zagouras, and T. F. Gajewski (2003)
J. Biol. Chem. 278, 17044-17052
   Abstract »    Full Text »    PDF »
Identification of RGS2 and Type V Adenylyl Cyclase Interaction Sites.
S. Salim, S. Sinnarajah, J. H. Kehrl, and C. W. Dessauer (2003)
J. Biol. Chem. 278, 15842-15849
   Abstract »    Full Text »    PDF »
Up-Regulation of Regulator of G Protein Signaling 4 Expression in a Model of Neuropathic Pain and Insensitivity to Morphine.
M. Garnier, P. F. Zaratin, G. Ficalora, M. Valente, L. Fontanella, M.-H. Rhee, K. J. Blumer, and M. A. Scheideler (2003)
J. Pharmacol. Exp. Ther. 304, 1299-1306
   Abstract »    Full Text »    PDF »
Temporal and Spatial Patterns of Ovarian Gene Transcription Following an Ovulatory Dose of Gonadotropin in the Rat.
L. L. Espey and J. S. Richards (2002)
Biol Reprod 67, 1662-1670
   Abstract »    Full Text »    PDF »
Cellular Regulation of RGS Proteins: Modulators and Integrators of G Protein Signaling.
S. Hollinger and J. R. Hepler (2002)
Pharmacol. Rev. 54, 527-559
   Abstract »    Full Text »    PDF »
Receptor-selective Effects of Endogenous RGS3 and RGS5 to Regulate Mitogen-activated Protein Kinase Activation in Rat Vascular Smooth Muscle Cells.
Q. Wang, M. Liu, B. Mullah, D. P. Siderovski, and R. R. Neubig (2002)
J. Biol. Chem. 277, 24949-24958
   Abstract »    Full Text »    PDF »
Identification of Quantitative Trait Loci That Affect Aggressive Behavior in Mice.
E. S. Brodkin, S. A. Goforth, A. H. Keene, J. A. Fossella, and L. M. Silver (2002)
J. Neurosci. 22, 1165-1170
   Abstract »    Full Text »    PDF »
Bridging with GAPs: Receptor Communication Through RGS Proteins.
K. M. Druey (2001)
Sci. STKE 2001, re14
   Abstract »    Full Text »    PDF »
Identification of Genes Expressed in the Amygdala During the Formation of Fear Memory.
O. Stork, S. Stork, H.-C. Pape, and K. Obata (2001)
Learn. Mem. 8, 209-219
   Abstract »    Full Text »    PDF »
Regulator of G Protein Signaling Proteins: Novel Multifunctional Drug Targets.
H. Zhong and R. R. Neubig (2001)
J. Pharmacol. Exp. Ther. 297, 837-845
   Abstract »    Full Text »
RGS2 blocks slow muscarinic inhibition of N-type Ca2+ channels reconstituted in a human cell line.
K. Melliti, U. Meza, and B. A Adams (2001)
J. Physiol. 532, 337-347
   Abstract »    Full Text »    PDF »
RGS2 Promotes Adipocyte Differentiation in the Presence of Ligand for Peroxisome Proliferator-activated Receptor gamma.
M. Nishizuka, K. Honda, T. Tsuchiya, T. Nishihara, and M. Imagawa (2001)
J. Biol. Chem. 276, 29625-29627
   Abstract »    Full Text »    PDF »
Mechanisms Governing Subcellular Localization and Function of Human RGS2.
S. P. Heximer, H. Lim, J. L. Bernard, and K. J. Blumer (2001)
J. Biol. Chem. 276, 14195-14203
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882