Functional association of the β₁ subunit with human cardiac (hH1) and rat skeletal muscle (μ1) sodium channel α subunits expressed in Xenopus oocytes

Native cardiac and skeletal muscle Na channels are complexes of α and β₁ subunits. While structural correlates for activation, inactivation, and permeation have been identified in the α subunit and the expression of α alone produces functional channels, β₁-deficient rat skeletal muscle (μ1) and brain Na channels expressed in Xenopus oocytes do not gate normally. In contrast, the requirement of a β₁ subunit for normal function of Na channels cloned from rat heart or human heart (hH1) has been disputed. Coinjection of rat brain β₁ subunit cRNA with hH1 (or μ1) α subunit cRNA into oocytes increased peak Na currents recorded 2 d after injection by 240% (295%) without altering the voltage dependence of activation. In μ1 channels, steady state inactivation was shifted to more negative potentials (by 6 mV, p < 0.01), but the shift of 2 mV was not significant for hH1 channels. Nevertheless, coexpression with β₁ subunit speeded the decay of macroscopic current of both isoforms. Ensemble average hH1 currents from cell-attached patches revealed that coexpression of β₁ increases the rate of inactivation (quantified by time to 75% decay of current; p < 0.01 at - 30, -40, and -50 mV). Use-dependent decay of hH1 Na current during repeated pulsing to -20 mV (1 s, 0.5 Hz) after a long rest was reduced to 16 ± 9% of the first pulse current in oocytes coexpressing α and β₁ subunits compared to 35 ± 8% use-dependent decay for oocytes expressing the α subunit alone. Recovery from inactivation of μ1 and hH1 Na currents after 1-s pulses to - 20 mV is multiexponential with three time constants; coexpression of β₁ subunit decreased all three recovery time constants. We conclude that the β₁ subunit importantly influences the function of Na channels produced by coexpression with either the hH1 or β₁ α subunits.