Altered responses to potassium in cerebellar neurons from weaver heterozygote mice.
The pleiotropic weaver disease is caused by the mutation of a single amino acid in the G-protein-linked inwardly rectifying K+ channel, GIRK2. In homozygous (wv/wv) animals, the disease is characterized by loss of cerebellar and dopaminergic mesencephalic neurons as well as testicular cells, which produce ataxia, fine tremors, and sterility, respectively. Heterozygous (wv/+) animals show no obvious motor impairments, although some loss of both cerebellar and dopaminergic neurons is observed and wv/+ males become sterile at 3.5 months of age. Abnormal influxes of Na+ and Ca2+ have been linked to cerebellar cell death in wv/wv animals, but it's not clear whether similar changes are observed in wv/+ animals. To discover whether changes in K+-channel function or intracellular Ca2+ concentrations ([Ca2+]i) play a role in the augmented cell loss observed in wv/+ animals when compared with +/+ animals, we studied cultured cerebellar granule cells prepared from either wv/+ or +/+ animals. Resting [Ca2+]i was elevated in wv/+ relative to +/+ animals. Further, depolarizations of cells with elevated K+ solutions elicited much smaller changes in [Ca2+]i in wv/+ animals than in +/+ animals, presumably due to altered GIRK2 channel function. Both wv/+ and +/+ cells showed similar changes in [Ca2+]i when cells were depolarized by glutamate (1 mM), suggesting that both glutamate receptors and Ca2+ channels were unchanged in wv/ + animals. In summary, our results suggest that wv/+ cerebellar granule cells exhibit elevated resting [Ca2+]i levels and altered K+-channel function, which may contribute to the developmental abnormalities and increased cell death observed.
Fox
A P
AP
The University of Chicago, Department of Pharmacological and Physiological Sciences, IL 60637, USA. Aaron@Drugs.bsd.uchicago.edu
Dlouhy
S
S
Ghetti
B
B
Hurley
J H
JH
Nucifora
P G
PG
Nelson
D J
DJ
Won
L
L
Heller
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018698:Glutamic Acid / Q000494:pharmacology; D006579:Heterozygote; D051379:Mice; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D018698:Glutamic Acid; D011188:Potassium; D002118:Calcium