Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABA B receptor signaling

Biswanath Maity, Adele Stewart, Jianqi Yang, Lipin Loo, David Sheff, Andrew J. Shepherd, Durga P. Mohapatra, Rory A. Fisher

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

γ-Aminobutyric acid (GABA) release from inhibitory interneurons located within the cerebellar cortex limits the extent of neuronal excitation in part through activation of metabotropic GABA B receptors. Stimulation of these receptors triggers a number of downstream signaling events, including activation of GIRK channels by the Gβγ dimer resulting in membrane hyperpolarization and inhibition of neurotransmitter release from presynaptic sites. Here, we identify RGS6, a member of the R7 subfamily of RGS proteins, as a key regulator of GABA BR signaling in cerebellum. RGS6 is enriched in the granule cell layer of the cerebellum along with neuronal GIRK channel subunits 1 and 2 where RGS6 forms a complex with known binding partners Gβ 5 and R7BP. Mice lacking RGS6 exhibit abnormal gait and ataxia characterized by impaired rotarod performance improved by treatment with a GABA BR antagonist. RGS6 -/- mice administered baclofen also showed exaggerated motor coordination deficits compared with their wild-type counterparts. Isolated cerebellar neurons natively expressed RGS6, GABA BR, and GIRK channel subunits, and cerebellar granule neurons from RGS6 -/- mice showed a significant delay in the deactivation kinetics of baclofen-induced GIRK channel currents. These results establish RGS6 as a key component of GABA BR signaling and represent the first demonstration of an essential role for modulatory actions of RGS proteins in adult cerebellum. Dysregulation of RGS6 expression in human patients could potentially contribute to loss of motor coordination and, thus, pharmacological manipulation of RGS6 levels might represent a viable means to treat patients with ataxias of cerebellar origin.

Original languageEnglish
Pages (from-to)4972-4981
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number7
DOIs
StatePublished - Feb 10 2012

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    Maity, B., Stewart, A., Yang, J., Loo, L., Sheff, D., Shepherd, A. J., Mohapatra, D. P., & Fisher, R. A. (2012). Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABA B receptor signaling. Journal of Biological Chemistry, 287(7), 4972-4981. https://doi.org/10.1074/jbc.M111.297218