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J. Biol. Chem., Vol. 283, Issue 25, 16985-16992, June 20, 2008

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The M1P1 Loop of TASK3 K2P Channels Apposes the Selectivity Filter and Influences Channel Function^*

Catherine E. Clarke¹², Emma L. Veale^¶1, Ken Wyse, Jamie I. Vandenberg, and Alistair Mathie^¶3

From the Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Central Avenue, Chatham Maritime, Kent ME4 4TB, United Kingdom, ^¶Biophysics Section, Blackett Laboratory, Division of Cell and Molecular Biology, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom, and Victor Chang Research Institute, University of New South Wales, Sydney, New South Wales 2010, Australia

Channels of the two-pore domain potassium (K2P) family contain two pore domains rather than one and an unusually long pre-pore extracellular linker called the M1P1 loop. The TASK (TASK1, TASK3, and TASK5) subfamily of K2P channels is regulated by a number of different pharmacological and physiological mediators. At pH 7.4 TASK3 channels are selectively blocked by zinc in a manner that is both pH_o- and [K]_o^-dependent. Mutation of both the Glu-70 residue in the M1P1 loop and the His-98 residue in the pore region abolished block, suggesting the two residues may contribute to a zinc binding site. Mutation of one Glu-70 residue and one His-98 residue to cysteine in TASK3 fixed concatamer channels gave currents that were enhanced by dithiothreitol and then potently blocked by cadmium, suggesting that spontaneous disulfide bridges could be formed between these two residues. Swapping the M1P1 loops of TASK1 and TASK3 channels showed that the M1P1 loop is also involved in channel regulation by pH. Therefore, the TASK3 M1P1 loop lies close to the pore, regulating TASK3 channel activity.

Received for publication, February 20, 2008 , and in revised form, April 15, 2008.

^* This work was supported in part by the Medical Research Council and the Australian Research Council (ARC). 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 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² An ARC postdoctoral fellow.

³ To whom correspondence should be addressed. Fax: 44-1634-883927; E-mail: a.a.mathie{at}kent.ac.uk.

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