NONSELECTIVE AND G(BETA-GAMMA)-INSENSITIVE WEAVER K+ CHANNELS

Homozygous weaver mice are profoundly ataxic because of the loss of gr anule cell neurons during cerebellar development. This granule cell lo ss appears to be caused by a genetic defect in the pore region (Gly(15 6) --> Ser) of the heterotrimeric guanine nucleotide-binding protein ( G protein)-gated inwardly rectifying potassium (K+) channel subunit (G IRK2). A related subunit, GIRK1, associates with GIRK2 to constitute a neuronal G protein-gated inward rectifier K+ channel. The weaver alle le of the GIRK2 subunit (wvGIRK2) caused loss of K+ selectivity when e xpressed either as wvGIRK2 homomultimers or as GIRK1-wvGIRK2 heteromul timers. The mutation also led to loss of sensitivity to G protein beta gamma dimers. Expression of wvGIRK2 subunits led to increased cell de ath, presumably as a result of basal nonselective channel opening.