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¹ Discipline of Physiology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia
² Centre for Advanced Biomedical Studies, University of South Australia, North Terrace, Adelaide, South Australia 5000, Australia

Transition metals block the muscle Cl^– channel ClC-1, which belongs to a large family of double-barreled Cl^– channels and transporters. In the Torpedo Cl^– channel ClC-0, Zn²⁺ block is closely related to the common gating mechanism that opens and closes both pores of the channel simultaneously, and the mutation C212S, which locks the common gate open, also eliminates the block. In ClC-1, however, previous results suggested that Zn²⁺ block is independent of gating, and that the cysteine residues involved in Zn²⁺ binding are in different positions to those that confer Zn²⁺ sensitivity on ClC-0. In this work, we show that Zn²⁺ block of ClC-1 is faster at hyperpolarized potentials where the channel is more likely to be in the closed state. Mutation C277S, equivalent to C212S in ClC-0, which locks the common gate in ClC-1 open, virtually eliminates Zn²⁺ block. A mutation, V321A, which reduces open probability of the common gate, facilitated Zn²⁺ block. These results demonstrate that Zn²⁺ block is state dependent, acting on the common gate. The extent of the block, however, is not a simple function of the open probability of the common gate. The Q₁₀ of 13 of the time course of Zn²⁺ block, which is significantly higher than the Q₁₀ of common gating transitions in WT ClC-1, suggests that Zn²⁺ binds to a very high temperature-dependent low-probability closed substate of the common gate, which has not yet been characterized in this channel.

(Received 30 May 2005; accepted after revision 4 July 2005; first published online 7 July 2005)
Corresponding author G. Rychkov: School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia. Email: grigori.rychkov{at}adelaide.edu.au

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