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The Journal of Neuroscience, September 1, 2002, 22(17):7462-7470

The Myotonia Congenita Mutation A331T Confers a Novel Hyperpolarization-Activated Gate to the Muscle Chloride Channel ClC-1

Maike Warnstedt¹, Chen Sun², Barbara Poser¹, Maria Jose Escriva¹, Lisbeth Tranebjærg^{2, 5}, Torberg Torbergsen³, Marijke van Ghelue⁴, and Christoph Fahlke^{1, 6}

¹ Institute of Physiology, Rheinisch-Westfälische Technische Hochschule Aachen, 52057 Aachen, Germany, Departments of ² Medical Genetics, ³ Neurology, and ⁴ Biochemistry, University Hospital of Tromsø, N-9038 Tromsø, Norway, ⁵ Department of Audiology, Hovedstadens Sygehusfællesskab, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen, Denmark, and Institute of Biochemistry and Medical Genetics, Institute of Medical Biochemistry and Genetics, University of Copenhagen, DK-2200 Copenhagen, Denmark, and ⁶ Centro de Estudios Cientificos (CECS), Valdivia, Chile

Mutations in the muscle chloride channel gene CLCN1 cause myotonia congenita, an inherited disorder of skeletal muscle excitability leading to a delayed relaxation after muscle contraction. Here, we examine the functional consequences of a novel disease-causing mutation that predicts the substitution of alanine by threonine at position 331 (A331T) by whole-cell patch-clamp recording of recombinant mutant channels. A331T hClC-1 channels exhibit a novel slow gate that activates during membrane hyperpolarization and closes at positive potentials. This novel gate acts in series with fast opening and closing transitions that are common to wild-type (WT) and mutant channels. Under conditions at which this novel gate is not activated, i.e., a holding potential of 0 mV, the typical depolarization-induced activation gating of WT hClC-1 was only slightly affected by the mutation. In contrast, A331T hClC-1 channels with an open slow gate display an altered voltage dependence of open probability. These novel gating features of mutant channels produce a decreased open probability at 85 mV, the normal muscle resting potential, leading to a reduced resting chloride conductance of affected muscle fibers. The A331T mutation causes an unprecedented alteration of ClC-1 gating and reveals novel processes defining transitions between open and closed states in ClC chloride channels.

Key words: chloride channels; ClCN1; gating; mutations; myotonia congenita; channelopathies

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22177462-09$05.00/0

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