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¹ Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232
² Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232
³ Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232

Address correspondence to Jeffrey R. Balser, Room 560 PRB (MRB II), Vanderbilt University School of Medicine, Nashville, TN 37232. Fax: (615) 936-0456; E-mail: jeff.balser{at}mcmail.vanderbilt.edu

Most voltage-gated K⁺ currents are relatively insensitive to extracellular Na⁺ (Na⁺_o), but Na⁺_o potently inhibits outward human ether-a-go-go–related gene (HERG)–encoded K⁺ channel current (Numaguchi, H., J.P. Johnson, Jr., C.I. Petersen, and J.R. Balser. 2000. Nat. Neurosci. 3:429–30). We studied wild-type (WT) and mutant HERG currents and used two strategic probes, intracellular Na⁺ (Na⁺_i) and extracellular Ba²⁺ (Ba²⁺_o), to define a site where Na⁺_o interacts with HERG. Currents were recorded from transfected Chinese hamster ovary (CHO-K1) cells using the whole-cell voltage clamp technique. Inhibition of WT HERG by Na⁺_o was not strongly dependent on the voltage during activating pulses. Three point mutants in the P-loop region (S624A, S624T, S631A) with intact K⁺ selectivity and impaired inactivation each had reduced sensitivity to inhibition by Na⁺_o. Quantitatively similar effects of Na⁺_i to inhibit HERG current were seen in the WT and S624A channels. As S624A has impaired Na⁺_o sensitivity, this result suggested that Na⁺_o and Na⁺_i act at different sites. Extracellular Ba²⁺ (Ba²⁺_o) blocks K⁺ channel pores, and thereby serves as a useful probe of K⁺ channel structure. HERG channel inactivation promotes relief of Ba²⁺ block (Weerapura, M., S. Nattel, M. Courtemanche, D. Doern, N. Ethier, and T. Hebert. 2000. J. Physiol. 526:265–278). We used this feature of HERG inactivation to distinguish between simple allosteric and pore-occluding models of Na⁺_o action. A remote allosteric model predicts that Na⁺_o will speed relief of Ba²⁺_o block by promoting inactivation. Instead, Na⁺_o slowed Ba²⁺ egress and Ba²⁺ relieved Na⁺_o inhibition, consistent with Na⁺_o binding to an outer pore site. The apparent affinities of the outer pore for Na⁺_o and K⁺_o as measured by slowing of Ba²⁺ egress were compatible with competition between the two ions for the channel pore in their physiological concentration ranges. We also examined the role of the HERG closed state in Na⁺_o inhibition. Na⁺_o inhibition was inversely related to pulsing frequency in the WT channel, but not in the pore mutant S624A.

Key Words: human ether-a-go-go-related gene • potassium ion channel • ion channel gating • sodium • barium

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