Episodic ataxia results from voltage-dependent potassium channels with altered functions

John P. Adelman; Chris T. Bond; Mauro Pessia; James Mayliet

doi:10.1016/0896-6273(95)90022-5

Episodic ataxia results from voltage-dependent potassium channels with altered functions

John P. Adelman
, Chris T. Bond
, Mauro Pessia
, James Mayliet

Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

208 Scopus citations

Abstract

Episodic ataxia (EA) is an autosomal dominant human disorder that produces persistent myokymia and attacks of generalized ataxia. Recently, familial EA has been linked to the voltage-dependent delayed rectifier, Kv1.1, on chromosome 12. Six EA families have been identified that carry distinct Kv1.1 missense mutations; all individuals are heterozygous. Expression in Xenopus oocytes demonstrates that two of the EA subunits form homomeric channels with altered gating properties. V408A channels have voltage dependence similar to that of wild-type channels, but with faster kinetics and increased C-type inactivation, while the voltage dependence of F1 84C channels is shifted 20 mV positive. The other four EA subunits do not produce functional homomeric channels but reduce the potassium current when coassembled with wild-type subunits. The results suggest a cellular mechanism underlying EA in which the affected nerve cells cannot efficiently repolarize following an action potential because of altered delayed rectifier function.

Original language	English (US)
Pages (from-to)	1449-1454
Number of pages	6
Journal	Neuron
Volume	15
Issue number	6
DOIs	https://doi.org/10.1016/0896-6273(95)90022-5
State	Published - Jan 1 1995

Funding

We thank Dr. Mike Litt for communication of the EA mutations prior to publication and for enthusiastic interactions. We also thank our colleagues Bruce Bean and Ed McCleskey for critical and insightful comments as well as Amela Brankovic and Wei-Bin Wu for Xenopus handling and oocyte preparation. This work was supported by National Institutes of Health grants to J. P. A. and J. M. and Telethon Italy to M. P.

Funders
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health

ASJC Scopus subject areas

General Neuroscience

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10.1016/0896-6273(95)90022-5

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title = "Episodic ataxia results from voltage-dependent potassium channels with altered functions",

abstract = "Episodic ataxia (EA) is an autosomal dominant human disorder that produces persistent myokymia and attacks of generalized ataxia. Recently, familial EA has been linked to the voltage-dependent delayed rectifier, Kv1.1, on chromosome 12. Six EA families have been identified that carry distinct Kv1.1 missense mutations; all individuals are heterozygous. Expression in Xenopus oocytes demonstrates that two of the EA subunits form homomeric channels with altered gating properties. V408A channels have voltage dependence similar to that of wild-type channels, but with faster kinetics and increased C-type inactivation, while the voltage dependence of F1 84C channels is shifted 20 mV positive. The other four EA subunits do not produce functional homomeric channels but reduce the potassium current when coassembled with wild-type subunits. The results suggest a cellular mechanism underlying EA in which the affected nerve cells cannot efficiently repolarize following an action potential because of altered delayed rectifier function.",

author = "Adelman, \{John P.\} and Bond, \{Chris T.\} and Mauro Pessia and James Mayliet",

note = "Funding Information: We thank Dr. Mike Litt for communication of the EA mutations prior to publication and for enthusiastic interactions. We also thank our colleagues Bruce Bean and Ed McCleskey for critical and insightful comments as well as Amela Brankovic and Wei-Bin Wu for Xenopus handling and oocyte preparation. This work was supported by National Institutes of Health grants to J. P. A. and J. M. and Telethon Italy to M. P.",

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AU - Adelman, John P.

AU - Bond, Chris T.

AU - Pessia, Mauro

AU - Mayliet, James

N1 - Funding Information: We thank Dr. Mike Litt for communication of the EA mutations prior to publication and for enthusiastic interactions. We also thank our colleagues Bruce Bean and Ed McCleskey for critical and insightful comments as well as Amela Brankovic and Wei-Bin Wu for Xenopus handling and oocyte preparation. This work was supported by National Institutes of Health grants to J. P. A. and J. M. and Telethon Italy to M. P.

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Episodic ataxia (EA) is an autosomal dominant human disorder that produces persistent myokymia and attacks of generalized ataxia. Recently, familial EA has been linked to the voltage-dependent delayed rectifier, Kv1.1, on chromosome 12. Six EA families have been identified that carry distinct Kv1.1 missense mutations; all individuals are heterozygous. Expression in Xenopus oocytes demonstrates that two of the EA subunits form homomeric channels with altered gating properties. V408A channels have voltage dependence similar to that of wild-type channels, but with faster kinetics and increased C-type inactivation, while the voltage dependence of F1 84C channels is shifted 20 mV positive. The other four EA subunits do not produce functional homomeric channels but reduce the potassium current when coassembled with wild-type subunits. The results suggest a cellular mechanism underlying EA in which the affected nerve cells cannot efficiently repolarize following an action potential because of altered delayed rectifier function.

AB - Episodic ataxia (EA) is an autosomal dominant human disorder that produces persistent myokymia and attacks of generalized ataxia. Recently, familial EA has been linked to the voltage-dependent delayed rectifier, Kv1.1, on chromosome 12. Six EA families have been identified that carry distinct Kv1.1 missense mutations; all individuals are heterozygous. Expression in Xenopus oocytes demonstrates that two of the EA subunits form homomeric channels with altered gating properties. V408A channels have voltage dependence similar to that of wild-type channels, but with faster kinetics and increased C-type inactivation, while the voltage dependence of F1 84C channels is shifted 20 mV positive. The other four EA subunits do not produce functional homomeric channels but reduce the potassium current when coassembled with wild-type subunits. The results suggest a cellular mechanism underlying EA in which the affected nerve cells cannot efficiently repolarize following an action potential because of altered delayed rectifier function.

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ER -

Episodic ataxia results from voltage-dependent potassium channels with altered functions

Abstract

Funding

ASJC Scopus subject areas

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