An aspartic acid residue important for voltage-dependent gating of human muscle chloride channels

Christoph Fahlke; Reinhardt Riidel; Nenad Mitrovic; Ming Zhou; Alfred L. George

doi:10.1016/0896-6273(95)90050-0

An aspartic acid residue important for voltage-dependent gating of human muscle chloride channels

Christoph Fahlke^*, Reinhardt Riidel, Nenad Mitrovic, Ming Zhou, Alfred L. George

^*Corresponding author for this work

Pharmacology

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

105 Scopus citations

Abstract

A point mutation (D136G) predicting the substitution of glycine for aspartate in position 136 of the human muscle CI^- channel (hCIC-1) causes recessive generalized myotonia. Heterologous expression of a recombinant D136G produces functional Cl^- channels with profound alterations in voltage-dependent gating, without concomitant changes in pore properties. The mutant exhibits slowly activating current upon hyperpolarization, in contrast to wild-type channels, which display time-dependent current decay (deactivation) at negative membrane potentials. Steady-state activation of D136G depends upon the transmembrane Cl^- gradient, reaching zero at voltages positive to the Cl^- reversal potential in physiological Cl^- distribution. This explains the reduced sarcolemmal Cl^- conductance that causes myotonia. The functional disturbances exhibited by D136G may stem from a defect in the CIC-1 voltage sensor.

Original language	English (US)
Pages (from-to)	463-472
Number of pages	10
Journal	Neuron
Volume	15
Issue number	2
DOIs	https://doi.org/10.1016/0896-6273(95)90050-0
State	Published - Aug 1995

Funding

All correspondence should be directed to A. L. G. We dedicate this work to Prof. Shirley H. Bryant on the occasion of his 70th birthday on February 24, 1995. We thank Dr. Frank Lehmann-Horn for valuable suggestions, Dr. Pedro Labarca for helpful comments on the manuscript, Ms. Traudl Hiller for expert preparation and injection of oocytes, and Ms. Margit Rudolf and Ms. Sigrun Sch~ifer for technical assistance. C. F. is indebted to Drs. Ricardo Delgado, Pedro Labarca, and Ramon Latorre for teaching him the treatment of oocytes during a visit in Chile. This work was supported by the Deutsche Forschungsgemeinschaft (Ru 138/17-3), the Muscular Dystrophy Association, and the Lucille P. Markey Charitable Trust. A. L. G. is a Lucille P. Markey Scholar. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC Section 1734 solely to indicate this fact.

ASJC Scopus subject areas

General Neuroscience

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title = "An aspartic acid residue important for voltage-dependent gating of human muscle chloride channels",

abstract = "A point mutation (D136G) predicting the substitution of glycine for aspartate in position 136 of the human muscle CI- channel (hCIC-1) causes recessive generalized myotonia. Heterologous expression of a recombinant D136G produces functional Cl- channels with profound alterations in voltage-dependent gating, without concomitant changes in pore properties. The mutant exhibits slowly activating current upon hyperpolarization, in contrast to wild-type channels, which display time-dependent current decay (deactivation) at negative membrane potentials. Steady-state activation of D136G depends upon the transmembrane Cl- gradient, reaching zero at voltages positive to the Cl- reversal potential in physiological Cl- distribution. This explains the reduced sarcolemmal Cl- conductance that causes myotonia. The functional disturbances exhibited by D136G may stem from a defect in the CIC-1 voltage sensor.",

author = "Christoph Fahlke and Reinhardt Riidel and Nenad Mitrovic and Ming Zhou and George, {Alfred L.}",

note = "Funding Information: All correspondence should be directed to A. L. G. We dedicate this work to Prof. Shirley H. Bryant on the occasion of his 70th birthday on February 24, 1995. We thank Dr. Frank Lehmann-Horn for valuable suggestions, Dr. Pedro Labarca for helpful comments on the manuscript, Ms. Traudl Hiller for expert preparation and injection of oocytes, and Ms. Margit Rudolf and Ms. Sigrun Sch~ifer for technical assistance. C. F. is indebted to Drs. Ricardo Delgado, Pedro Labarca, and Ramon Latorre for teaching him the treatment of oocytes during a visit in Chile. This work was supported by the Deutsche Forschungsgemeinschaft (Ru 138/17-3), the Muscular Dystrophy Association, and the Lucille P. Markey Charitable Trust. A. L. G. is a Lucille P. Markey Scholar. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked {"}advertisement{"} in accordance with 18 USC Section 1734 solely to indicate this fact.",

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AU - Zhou, Ming

AU - George, Alfred L.

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N2 - A point mutation (D136G) predicting the substitution of glycine for aspartate in position 136 of the human muscle CI- channel (hCIC-1) causes recessive generalized myotonia. Heterologous expression of a recombinant D136G produces functional Cl- channels with profound alterations in voltage-dependent gating, without concomitant changes in pore properties. The mutant exhibits slowly activating current upon hyperpolarization, in contrast to wild-type channels, which display time-dependent current decay (deactivation) at negative membrane potentials. Steady-state activation of D136G depends upon the transmembrane Cl- gradient, reaching zero at voltages positive to the Cl- reversal potential in physiological Cl- distribution. This explains the reduced sarcolemmal Cl- conductance that causes myotonia. The functional disturbances exhibited by D136G may stem from a defect in the CIC-1 voltage sensor.

AB - A point mutation (D136G) predicting the substitution of glycine for aspartate in position 136 of the human muscle CI- channel (hCIC-1) causes recessive generalized myotonia. Heterologous expression of a recombinant D136G produces functional Cl- channels with profound alterations in voltage-dependent gating, without concomitant changes in pore properties. The mutant exhibits slowly activating current upon hyperpolarization, in contrast to wild-type channels, which display time-dependent current decay (deactivation) at negative membrane potentials. Steady-state activation of D136G depends upon the transmembrane Cl- gradient, reaching zero at voltages positive to the Cl- reversal potential in physiological Cl- distribution. This explains the reduced sarcolemmal Cl- conductance that causes myotonia. The functional disturbances exhibited by D136G may stem from a defect in the CIC-1 voltage sensor.

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An aspartic acid residue important for voltage-dependent gating of human muscle chloride channels

Abstract

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