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Regulator of G Protein Signaling 6 (RGS6) Protein Ensures Coordination of Motor Movement by Modulating GABAB Receptor Signaling
Journal article   Open access   Peer reviewed

Regulator of G Protein Signaling 6 (RGS6) Protein Ensures Coordination of Motor Movement by Modulating GABAB Receptor Signaling

Biswanath Maity, Adele Stewart, Jianqi Yang, Lipin Loo, David Sheff, Andrew J Shepherd, Durga P Mohapatra and Rory A Fisher
The Journal of biological chemistry, Vol.287(7), pp.4972-4981
02/10/2012
DOI: 10.1074/jbc.M111.297218
PMCID: PMC3281673
PMID: 22179605
url
https://doi.org/10.1074/jbc.M111.297218View
Published (Version of record) Open Access

Abstract

Background: GABA B R signaling blocks neuronal firing ensuring appropriate cerebellar cortex output. Results: Loss of RGS6 results in ataxia rescued by a GABA B R antagonist and enhanced GABA B R-GIRK current in neurons. Conclusion: RGS6 is an essential component of GABA signaling in cerebellum and required for motor coordination. Significance: RGS6 dysregulation could result in cerebellar ataxia, and thus, it might represent a novel target for pharmacological intervention. 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 B R 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 B R antagonist. RGS6 −/− mice administered baclofen also showed exaggerated motor coordination deficits compared with their wild-type counterparts. Isolated cerebellar neurons natively expressed RGS6, GABA B R, 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 B R 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.
 Cerebellum GABABR GABA receptors RGS proteins GIRK G protein-coupled receptors (GPCRs) G proteins Cell Biology

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