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Carboxy-Terminal Truncations Modify the Outer Pore Vestibule of Muscle Chloride Channels

Simon Hebeisen ^* and Christoph Fahlke ^* 

^* Department of Physiology, RWTH Aachen, Aachen, Germany; and Centro de Estudios Cientificos, Valdivia, Chile

Correspondence: Address reprint requests to Christoph Fahlke, Abteilung Neurophysiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Tel.: 49-511-532-2774; Fax: 49-511-532-2776; E-mail: fahlke.christoph{at}mh-hannover.de.

Mammalian ClC-type chloride channels have large cytoplasmic carboxy-terminal domains whose function is still insufficiently understood. We investigated the role of the distal part of the carboxy-terminus of the muscle isoform ClC-1 by constructing and functionally evaluating two truncation mutants, R894X and K875X. Truncated channels exhibit normal unitary conductances and anion selectivities but altered apparent anion binding affinities in the open and in the closed state. Since voltage-dependent gating is strictly coupled to ion permeation in ClC-1 channels, the changed pore properties result in different fast and slow gating. Full length and truncated channels also differed in methanethiosulphonate (MTS) modification rate constants of an engineered cysteine at position 231 near the selectivity filter. Our data demonstrate that the carboxy-terminus of ClC channels modifies the conformation of the outer pore vestibule.

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