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Binding Site in Eag Voltage Sensor Accommodates a Variety of Ions and is Accessible in Closed Channel

Department of Physiology and Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

Correspondence: Address reprint requests to Diane M. Papazian, PhD, Dept. of Physiology, Box 951751, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751. Tel.: 310-206-7043; Fax: 310-206-5661; E-mail: papazian{at}mednet.ucla.edu.

In ether-à-go-go K⁺ channels, voltage-dependent activation is modulated by ion binding to a site located in an extracellular-facing crevice between transmembrane segments S2 and S3 in the voltage sensor. We find that acidic residues D278 in S2 and D327 in S3 are able to coordinate a variety of divalent cations, including Mg²⁺, Mn²⁺, and Ni²⁺, which have qualitatively similar functional effects, but different half-maximal effective concentrations. Our data indicate that ions binding to individual voltage sensors in the tetrameric channel act without cooperativity to modulate activation gating. We have taken advantage of the unique phenotype of Ni²⁺ in the D274A channel, which contains a mutation of a nonbinding site residue, to demonstrate that ions can access the binding site from the extracellular solution when the voltage sensor is in the resting conformation. Our results are difficult to reconcile with the x-ray structure of the KvAP K⁺ channel, in which the binding site residues are widely separated, and with the hydrophobic paddle model for voltage-dependent activation, in which the voltage sensor domain, including the S3–S4 loop, is near the cytoplasmic side of the membrane in the closed channel.

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