title: Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABAB receptor signaling.
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(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.
authors.affiliation: Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Biswanath
authors.initials: B
authors.lastname: Maity
authors.forename: Adele
authors.initials: A
authors.lastname: Stewart
authors.forename: Jianqi
authors.initials: J
authors.lastname: Yang
authors.forename: Lipin
authors.initials: L
authors.lastname: Loo
authors.forename: David
authors.initials: D
authors.lastname: Sheff
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Shepherd
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
authors.forename: Rory A
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002524:Cerebellar Ataxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008124:Locomotion; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D058786:GABA-B Receptor Agonists; D044387:GTP-Binding Protein beta Subunits; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C499440:R7BP protein, mouse; D020710:RGS Proteins; C400194:RGS6 protein, human; D018080:Receptors, GABA-B; C485692:Rgs6 protein, mouse; D001418:Baclofen