RGS9-2 modulates D2 dopamine receptor-mediated Ca2+ channel inhibition in rat striatal cholinergic interneurons
- Theresa M. Cabrera-Vera†,‡,
- Salvador Hernandez†,§,
- Laurie R. Earls¶,
- Martina Medkova†,‡,
- Anna K. Sundgren-Andersson†,‡,
- D. James Surmeier†,§, and
- Heidi E. Hamm†,‡,¶,∥
- †Institute for Neuroscience and Departments of ‡Molecular Pharmacology and Biological Chemistry and §Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and ¶Department of Pharmacology, Vanderbilt University, Nashville, TN 37232
-
Communicated by John H. Exton, Vanderbilt University School of Medicine, Nashville, TN, October 6, 2004 (received for review November 23, 2003)
Abstract
Regulator of G protein signaling (RGS) proteins negatively regulate receptor-mediated second messenger responses by enhancing the GTPase activity of Gα subunits. We describe a receptor-specific role for an RGS protein at the level of an individual brain neuron. RGS9-2 and Gβ5 mRNA and protein complexes were detected in striatal cholinergic and γ-aminobutyric acidergic neurons. Dialysis of cholinergic neurons with RGS9 constructs enhanced basal Ca2+ channel currents and reduced D2 dopamine receptor modulation of Cav2.2 channels. These constructs did not alter M2 muscarinic receptor modulation of Cav2.2 currents in the same neuron. The noncatalytic DEP-GGL domain of RGS9 antagonized endogenous RGS9-2 activity, enhancing D2 receptor modulation of Ca2+ currents. In vitro, RGS9 constructs accelerated GTPase activity, in agreement with electrophysiological measurements, and did so more effectively at Go than Gi. These results implicate RGS9-2 as a specific regulator of dopamine receptor-mediated signaling in the striatum and identify a role for GAP activity modulation by the DEP-GGL domain.
Footnotes
-
↵ ∥ To whom correspondence should be addressed. E-mail: heidi.hamm{at}vanderbilt.edu.
-
Author contributions: M.M., D.J.S., and H.E.H. designed research; T.M.C.-V., S.H., M.M., and A.K.S.-A. performed research; T.M.C.-V., M.M., D.J.S., and H.E.H. analyzed data; and T.M.C.-V., L.R.E., M.M., D.J.S., and H.E.H. wrote the paper.
-
Abbreviations: RGS, regulators of G protein signaling; NPA, R(-)-propylnorapomorphine.
- Copyright © 2004, The National Academy of Sciences
