Evidence of elevated intracellular calcium levels in weaver homozygote mice

• Published in: The Journal of physiology Vol. 524; no. 2; pp. 447 - 455
• Main Authors: Harkins, A. B., Dlouhy, S., Ghetti, B., Cahill, A. L., Won, L., Heller, B., Heller, A., Fox, A. P.
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15.04.2000; Blackwell Science Ltd; Blackwell Science Inc
• Subjects: Animals; Calcium - metabolism; Cell Survival - drug effects; Cells, Cultured; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - metabolism; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Homozygote; Lidocaine - analogs & derivatives; Lidocaine - pharmacology; Mice; Mice, Neurologic Mutants; Neurons - metabolism; Original; Potassium - pharmacology; Potassium Channel Blockers; Potassium Channels - genetics; Potassium Channels, Inwardly Rectifying; Stimulation, Chemical
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1111/j.1469-7793.2000.t01-2-00447.x

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 may involve constitutive influx of Na + and Ca 2+ into the neurons. We found that resting [Ca 2+ ] i was dramatically higher in cerebellar neurons from weaver mice compared to wild-type neurons. High-K + stimuli elicited much smaller changes in [Ca 2+ ] i in weaver cerebellar neurons compared to wild-type neurons. weaver cerebellar granule cells could be rescued from cell death by the GIRK2 wv cationic channel blocker, QX-314. QX-314 lowered resting intracellular Ca 2+ levels in weaver cerebellar granule cells. These results suggest that changes in resting [Ca 2+ ] i levels and alterations in K + channel function are most likely to contribute to the developmental abnormalities and increased cerebellar cell death observed in weaver mice.