EPISODIC ATAXIA MUTATIONS IN KV1.1 ALTER POTASSIUM CHANNEL FUNCTION BY DOMINANT-NEGATIVE EFFECTS OR HAPLOINSUFFICIENCY

Subunits of the voltage-gated potassium channel Kv1.1 containing mutat ions responsible for episodic ataxia (EA), a human inherited neurologi cal disease, were expressed in Xenopus oocytes. Five EA subunits forme d functional homomeric channels with lower current amplitudes and alte red gating properties compared with wild type. Two EA mutations locate d in the first cytoplasmic loop, R239S and F2491, yielded minimal or n o detectable current, and Western blot analysis showed reduced protein levels. Coinjection of equal amounts of EA and wildtype mRNAs, mimick ing the heterozygous condition, resulted in current amplitudes and gat ing properties that were intermediate between wild-type and EA homomer ic channels, suggesting that heteromeric channels are formed with a mi xed stoichiometry of EA and wild-type subunits. To examine the relativ e contribution of EA subunits in forming heteromeric EA and wild-type channels, each EA subunit was made insensitive to TEA, TEA-tagged, and coexpressed with wild-type subunits. TEA-tagged R239S and F2491 induc ed the smallest shift in TEA sensitivity compared with homomeric wild- type channels, whereas the other TEA-tagged EA subunits yielded TEA se nsitivities similar to coexpression of wild-type and TEA-tagged wild-t ype subunits, Taken together, these results show that the different mu tations in Kv1.1 affect channel function and indicate that both domina nt negative effects and haplotype insufficiency may result in the symp toms of EA.