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This Article Full Text Full Text (PDF) All Versions of this Article: 558/3/729    most recent jphysiol.2004.065193v1 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 Mullins, F. M. Articles by Balser, J. R. Search for Related Content PubMed PubMed Citation Articles by Mullins, F. M. Articles by Balser, J. R.

Departments of
¹ Pharmacology
² Anaesthesiology
³ Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

We have studied the interaction between extracellular K⁺ (K⁺_o) and extracellular Na⁺ (Na⁺_o) in human ether-à-go-go related gene (HERG)-encoded K⁺ channels expressed in Chinese hamster ovary (CHO-K1) cells, using the whole-cell voltage clamp technique. Prior studies indicate that Na⁺_o potently inhibits HERG current (IC₅₀ 3 mM) by binding to an outer pore site, and also speeds recovery from inactivation. In this study, we sought to explore the relationship between the Na⁺_o effect on recovery and Na⁺_o inhibition of HERG current, and to determine whether inactivation gating plays a critical role in Na⁺_o inhibition of HERG current. Na⁺_o concentration–response relationships for current inhibition and speeding of recovery were different, with Na⁺_o less potent at speeding recovery. Na⁺_o inhibition of HERG current was relieved by physiological [K⁺]_o, while Na⁺_o speeded recovery from inactivation similarly in the absence or presence of physiological [K⁺]_o. To examine the link between Na⁺_o block and inactivation using an independent approach, we studied hyperpolarization-activated currents uncoupled from inactivation in the S4–S5 linker mutant D540K. Depolarization-activated D540K currents were inhibited by Na⁺_o, while hyperpolarization-activated currents were augmented by Na⁺_o. This result reveals a direct link between Na⁺_o inhibition and a depolarization-induced conformational change, most likely inactivation. We attempted to simulate the disparate concentration–response relationships for the two effects of Na⁺_o using a kinetic model that included Na⁺_o site(s) affected by permeation and gating. While a model with only a single dynamic Na⁺_o site was inadequate, a model with two distinct Na⁺_o sites was sufficient to reproduce the data.

(Received 23 March 2004; accepted after revision 27 May 2004; first published online 28 May 2004)
Corresponding author J. R. Balser: Room 560 PRB (MRB II), Vanderbilt University School of Medicine, Nashville, TN 37232, USA.  Email: jeff.balser{at}mcmail.vanderbilt.edu

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