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This Article Full Text Full Text (PDF) All Versions of this Article: 567/3/737    most recent jphysiol.2005.089094v1 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 Fernandez, D. Articles by Sanguinetti, M. C Search for Related Content PubMed PubMed Citation Articles by Fernandez, D. Articles by Sanguinetti, M. C

¹ Department of Physiology and Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112-5000, USA

Cd²⁺ slows the rate of activation, accelerates the rate of deactivation and shifts the half-points of voltage-dependent activation (V_0.5,act) and inactivation (V_0.5,inact) of human ether-à-go-go-related gene (hERG) K⁺ channels. To identify specific Cd²⁺-binding sites on the hERG channel, we mutated potential Cd²⁺-coordination residues located in the transmembrane domains or extracellular loops linking these domains, including five Cys, three His, nine Asp and eight Glu residues. Each residue was individually substituted with Ala and the resulting mutant channels heterologously expressed in Xenopus oocytes and their biophysical properties determined with standard two-microelectrode voltage-clamp technique. Cd²⁺ at 0.5 mM caused a +36 mV shift of V_0.5,act and a +18 mV shift of V_0.5,inact in wild-type channels. Most mutant channels had a similar sensitivity to 0.5 mM Cd²⁺. Mutation of single Asp residues located in the S2 (D456, D460) or S3 (D509) domains reduced the Cd²⁺-induced shift in V_0.5,act, but not V_0.5,inact. Combined mutations of two or three of these key Asp residues nearly eliminated the shift induced by 0.5 mM Cd²⁺. Mutation of D456, D460 and D509 also reduced the comparatively low-affinity effects of Ca²⁺ and Mg²⁺ on V_0.5,act. Extracellular Cd²⁺ modulates hERG channel activation by binding to a coordination site formed, at least in part, by three Asp residues.

(Received 22 April 2005; accepted after revision 23 June 2005; first published online 23 June 2005)
Corresponding author M. C. Sanguinetti: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112-5000, USA. Email: sanguinetti{at}cvrti.utah.edu

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