FUNCTIONAL ASSOCIATION OF THE BETA(1) SUBUNIT WITH HUMAN CARDIAC (HH1) AND RAT SKELETAL-MUSCLE (MU-1) SODIUM-CHANNEL ALPHA-SUBUNITS EXPRESSED IN XENOPUS OOCYTES

Native cardiac and skeletal muscle Na channels are complexes of alpha and beta(1) subunits. While structural correlates for activation, inac tivation, and permeation have been identified in the alpha subunit and the expression of alpha alone produces functional channels, beta(1)-d eficient rat skeletal muscle (mu 1) and brain Na channels expressed in Xenopus oocytes do not gate normally. In contrast, the requirement of a beta(1) subunit for normal function of Na channels cloned from rat heart or human heart (hH1) has been disputed. Coinjection of rat brain beta(1) subunit cRNA with hH1 (or mu 1) alpha subunit cRNA into oocyt es increased peak Na currents recorded 2 d after injection by 240% (22 5%) without altering the voltage dependence of activation. In mu 1 cha nnels, steady state inactivation was shifted to more negative potentia ls (by 6 mV, p < 0.01), but the shift of 2 mV was not significant for hH1 channels. Nevertheless, coexpression with beta(1) subunit speeded the decay of macroscopic current of both isoforms. Ensemble average hH 1 currents from cell-attached patches revealed that coexpression of be ta(1) increases the rate of inactivation (quantified by time to 75% de cay 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) aft er a long rest was reduced to 16 +/- 2% of the first pulse current in oocytes coexpressing alpha and beta(1) subunits compared to 35 +/- 8% use-dependent decay for oocytes expressing the or subunit alone. Recov ery from inactivation of mu 1 and hH1 Na currents after 1-s pulses to -20 mV is multiexponential with three time constants; coexpression of beta(1) subunit decreased all three recovery time constants. We conclu de that the beta(1) subunit importantly influences the function of Na channels produced by coexpression with either the hH1 or mu 1 alpha su bunits.