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.