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This Article Full Text Full Text (PDF) All Versions of this Article: 562/3/687    most recent jphysiol.2004.079020v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by O'Connell, A. D Articles by Hunter, M. Search for Related Content PubMed PubMed Citation Articles by O'Connell, A. D Articles by Hunter, M.

¹ School of Biomedical Sciences, Worsley Building, University of Leeds, Leeds LS2 9JT, UK

The acid-sensitive K⁺ channel, TASK1 is a member of the K⁺-selective tandem-pore domain (K2P) channel family. Like many of the K2P channels, TASK1 is relatively insensitive to conventional channel blockers such as Ba²⁺. In this paper we report the impact of mutating the pore-neighbouring histidine residues, which are involved in pH sensing, on the sensitivity to blockade by Ba²⁺ and Cs⁺; additionally we compare the selectivity of these channels to extracellular K⁺, Na⁺ and Rb⁺. H98D and H98N mutants showed reduced selectivity for K⁺ over both Na⁺ and Rb⁺, and significant permeation of Rb⁺. This enhanced permeability must reflect changes in the structure or flexibility of the selectivity filter. Blockade by Ba²⁺ and Cs⁺ was voltage-dependent, indicating that both ions block within the pore. In 100 mM K⁺, the K_D at 0 mV for Ba²⁺ was 36 ± 10 mM (n = 6), whilst for Cs⁺ it was 20 ± 6.0 mM (n = 5). H98D was more sensitive to Ba²⁺ than the wild-type (WT); in addition, the site at which Ba²⁺ appears to bind was altered (WT: , 0.64 ± 0.16, n = 6; H98D: , 0.16 ± 0.03, n = 5, statistically different from WT; H98N: , 0.58 ± 0.09, not statistically different from WT). Thus, the pore-neighbouring residue H98 contributes not only to the pH sensitivity of TASK1, but also to the structure of the conduction pathway.

(Received 11 November 2004; accepted after revision 7 December 2004; first published online 20 December 2004)
Corresponding author M. Hunter: School of Biomedical Sciences, Worsley Building, University of Leeds, Leeds LS2 9JT, UK. Email: m.hunter{at}leeds.ac.uk

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