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The Journal of Neuroscience, April 15, 1998, 18(8):2842-2848
Episodic Ataxia Mutations in Kv1.1 Alter Potassium Channel
Function by Dominant Negative Effects or Haploinsufficiency
Patricia
Zerr1,
John P.
Adelman1, and
James
Maylie2
1 Vollum Institute and 2 Department of
Obstetrics and Gynecology, Oregon Health Sciences University, Portland,
Oregon 97201
Subunits of the voltage-gated potassium channel Kv1.1 containing
mutations responsible for episodic ataxia (EA), a human inherited neurological disease, were expressed in Xenopus oocytes.
Five EA subunits formed functional homomeric channels with lower
current amplitudes and altered gating properties compared with wild
type. Two EA mutations located in the first cytoplasmic loop, R239S and
F249I, yielded minimal or no detectable current, and Western blot
analysis showed reduced protein levels. Coinjection of equal amounts of
EA and wild-type mRNAs, mimicking the heterozygous condition, resulted
in current amplitudes and gating properties that were intermediate
between wild-type and EA homomeric channels, suggesting that
heteromeric channels are formed with a mixed stoichiometry of EA and
wild-type subunits. To examine the relative 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 F249I induced the smallest shift in TEA
sensitivity compared with homomeric wild-type channels, whereas the
other TEA-tagged EA subunits yielded TEA sensitivities similar to
coexpression of wild-type and TEA-tagged wild-type subunits. Taken
together, these results show that the different mutations in Kv1.1
affect channel function and indicate that both dominant negative
effects and haplotype insufficiency may result in the symptoms of
EA.
Key words:
episodic ataxia; neurological disease; K channel; oocyte
expression; haploinsufficiency; dominant negative effects
Copyright © 1998 Society for Neuroscience 0270-6474/98/1882842-07$05.00/0
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