The intracellular domain of the beta 2 subunit modulates the gating of cardiac Na(v)1.5 channels

We have previously shown that the transmembrane segment plus either the extracellular or intracellular domain of the beta 1 subunit are required to modify cardiac Na(v)1.5 channels. In this study, we coexpressed the intracellular domain of the beta 2 subunit in a beta 1/beta 2 chimera with Na(v)1.5 channels in Xenopus oocytes and obtained an atypical recovery behavior of Na(v)1.5 channels not reported before for other Na+ channels: Recovery times of up to 20 ms at -20 mV produced a similar fast recovery as observed for Na(v)1.5/beta 1 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 beta 2 intracellular domain. These results describe the first functional effects of a beta 2 subunit region on Na(v)1.5 channels and suggest a novel closed state in cardiac Na+ channels accessible at hyperpolarized potentials.