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Regulator of G Protein Signaling 6 (RGS6) ensures coordination of motor movement by modulating GABAB Receptor (GABABR) signaling

Inhibitory interneurons located within the cerebellar cortex release GABA, which limits neuronal excitation in part through activation of metabatropic GABABRs. Here, we identify RGS6, a member of the R7 subfamily of RGS proteins, as a key modulator of GABABR signaling in cerebellum. RGS6−/− mice exhibit abnormal gait and ataxia characterized by impaired rotarod performance that can be partially rescued by administration of a GABABR antagonist. In addition, RGS6−/− mice treated with baclofen, a GABABR agonist, show exaggerated motor coordination deficits on the rotarod compared to their wild type counterparts. Stimulation of GABABRs triggers a number of signaling events downstream of G protein activation including Gβγ subunit activation of G protein‐coupled inwardly rectifying potassium (GIRK) channels. Indeed, 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 Gβ5 and R7‐binding protein (R7BP), which stabilize and promote membrane association of R7 family members, respectively. Cerebellar granule neurons isolated from RGS6−/− mice showed a significant delay in the deactivation kinetics of baclofen‐induced GIRK currents. These results establish RGS6 as a key modulator of GABABR signaling, providing the first demonstration of an essential role for RGS proteins in cerebellar function.