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The Intracellular Domain of the ß2 Subunit Modulates the Gating of Cardiac Na_v1.5 Channels

Institute of Physiology II, Friedrich Schiller University, Jena, Germany

Correspondence: Address reprint requests to Thomas Zimmer, PhD, Institute of Physiology II, Friedrich Schiller University Kollegiengasse 9, 07743 Jena, Germany. Tel.: 49-3641-934372; Fax: 49-3641-933202; E-mail: thomas.zimmer{at}mti.uni-jena.de.

We have previously shown that the transmembrane segment plus either the extracellular or intracellular domain of the ß1 subunit are required to modify cardiac Na_v1.5 channels. In this study, we coexpressed the intracellular domain of the ß2 subunit in a ß1/ß2 chimera with Na_v1.5 channels in Xenopus oocytes and obtained an atypical recovery behavior of Na_v1.5 channels not reported before for other Na⁺ channels: Recovery times of up to 20 ms at –120 mV produced a similar fast recovery as observed for Na_v1.5/ß1 channels, but the current amplitude decreased again at longer recovery times and reached a steady-state level after 1–2 s with current amplitudes of only 43 ± 2% of the value at 20 ms. Current reduction was accompanied by slowed inactivation and by a shift of steady-state activation toward depolarized potentials by 9 mV. All effects were reversible and they were not seen when deleting the ß2 intracellular domain. These results describe the first functional effects of a ß2 subunit region on Na_v1.5 channels and suggest a novel closed state in cardiac Na⁺ channels accessible at hyperpolarized potentials.