HETEROMULTIMERIZATION OF G-PROTEIN-GATED INWARDLY RECTIFYING K+ CHANNEL PROTEINS GIRK1 AND GIRK2 AND THEIR ALTERED EXPRESSION IN WEAVER BRAIN

The weaver (wv) gene (GIRK2) is a member of the G-protein-gated inward ly rectifying potassium (GIRK) channel family, known effecters in the signal transduction pathway of neurotransmitters such as acetylcholine , dopamine, opioid peptides, and substance P in modulation of neurotra nsmitter release and neuronal excitability. GIRK2 immunoreactivity is found in but not limited to brain regions known to be affected in wv m ice, such as the cerebellar granule cells and dopaminergic neurons in the substantia nigra pars compacta. It is also observed in the ventral tegmental area, hippocampus, cerebral cortex, and thalamus. GIRK2 and GIRK1, a related family member, have overlapping yet distinct distrib utions in rat and mouse brains. In regions where both channel proteins are expressed, such as the cerebral cortex, hippocampus, and cerebell um, they can be co-immunoprecipitated, indicating that they interact t o form heteromeric channels in vivo. In the brain of the wv mouse, GIR K2 expression is decreased dramatically. In regions where GIRK1 and GI RK2 distributions overlap, both GIRK1 and GIRK2 expressions are severe ly disrupted, probably because of their co-assembly. The expression pa tterns of these GIRK channel subunits provide a basis for consideratio n of the machinery for neuronal signaling as well as the differential effects of the wv mutation in various neurons.