Evidence of elevated intracellular calcium levels in weaver homozygote mice

1. A mutation in the G-protein-linked, inwardly rectifying K+ channel GIRK2 leads to the loss of cerebellar and dopaminergic mesencephalic neurons in weaver mice. The steps leading to cell death are not well understood but ma y involve constitutive influx of Na+ and Ca2+ into the neurons. 2. We found that resting [Ca2+](i) was dramatically higher in cerebellar ne urons from weaver mice compared to wild-type neurons. 3. High-K+ stimuli elicited much smaller changes in [Ca2+](i) in weaver cer ebellar neurons compared to wild-type neurons. 4. weaver cerebellar granule cells could be rescued from cell death by the GIRK2wv cationic channel blocker, QX-314. 5. QX-314 lowered resting intracellular Ca2+ levels in weaver cerebellar gr anule cells. 6. These results suggest that changes in resting [Ca2+](i) levels and alter ations in K+ channel function are most likely to contribute to the developm ental abnormalities and increased cerebellar cell death observed in weaver mice.