Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2.
G protein-gated, inwardly rectifying K+ channels (GIRK) are effectors of G protein-coupled receptors for neurotransmitters and hormones and may play an important role in the regulation of neuronal excitability. GIRK channels may be important in neurodevelopment, as suggested by the recent finding that a point mutation in the pore region of GIRK2 (G156S) is responsible for the weaver (wv) phenotype. The GIRK2 G156S gene gives rise to channels that exhibit a loss of K+ selectivity and may also exert dominant-negative effects on G(betagamma)-activated K+ currents. To investigate the physiological role of GIRK2, we generated mutant mice lacking GIRK2. Unlike wv/wv mutant mice, GIRK2 -/- mice are morphologically indistinguishable from wild-type mice, suggesting that the wv phenotype is likely due to abnormal GIRK2 function. Like wv/wv mice, GIRK2 -/- mice have much reduced GIRK1 expression in the brain. They also develop spontaneous seizures and are more susceptible to pharmacologically induced seizures using a gamma-aminobutyric acid antagonist. Moreover, wv/- mice exhibit much milder cerebellar abnormalities than wv/wv mice, indicating a dosage effect of the GIRK2 G156S mutation. Our results indicate that the weaver phenotypes arise from a gain-of-function mutation of GIRK2 and that GIRK1 and GIRK2 are important mediators of neuronal excitability in vivo.
Signorini
S
S
Laboratory of Metabolic Diseases, Rockefeller University, New York, NY 10021, USA.
Liao
Y J
YJ
Duncan
S A
SA
Jan
L Y
LY
Stoffel
M
M
D000818:Animals; D001923:Brain Chemistry; D002531:Cerebellum / Q000737:chemistry / Q000254:growth & development*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018756:GABA Antagonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D018628:Gene Dosage; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D010433:Pentylenetetrazole / Q000494:pharmacology; D010641:Phenotype; D017354:Point Mutation; D015221:Potassium Channels / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger / Q000032:analysis; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018756:GABA Antagonists; C497066:KCNJ3 protein, human; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D019204:GTP-Binding Proteins; D010433:Pentylenetetrazole