Coexpression of beta 1 with cardiac sodium channel alpha subunits in oocytes decreases lidocaine block.
Coexpression of the rat beta 1 subunit with rat brain and skeletal muscle sodium channel alpha subunits in Xenopus oocytes normalizes currents by accelerating sodium current decay kinetics, shifting steady state availability relationships, and accelerating recovery from inactivation. Unlike brain and skeletal muscle, the heart alpha subunit expressed without beta 1 has native-like decay kinetics in oocytes. Messenger RNA for beta 1 has been found in heart, but whether and how it affects cardiac sodium channel function are unclear. We studied coexpression of human heart alpha subunit with beta 1 in Xenopus oocytes using two microelectrode voltage-clamp and macropatch techniques. Coexpression with beta 1 caused a significant positive shift of 3-7 mV in the midpoint of the steady state inactivation relationship but did not affect single-channel conductance, activation, current decay, or recovery from inactivation. Sensitivity to lidocaine block, however, was decreased for both resting state block (Kd = 0.5-1.3 mM) and phasic block in response to pulse trains, but inactivated state block was not affected (Kd = approximately 10 microM). Coexpression with beta 1 increased the rate of recovery from lidocaine block, which accounted for the major part of the observed differences in tonic and phasic block. A beta 1 construct with the cytoplasmic tail removed also produced these effects, demonstrating that the beta 1 cytoplasmic tail was not involved in altering lidocaine block. We conclude that the beta 1 subunit is capable of affecting function of the cardiac sodium channel in oocytes by decreasing tonic and phasic lidocaine block with small effects on gating.
Makielski
J C
JC
Cardiac Electrophysiology Laboratories, University of Chicago, Illinois 60637, USA.
Limberis
J T
JT
Chang
S Y
SY
Fan
Z
Z
Kyle
J W
JW
D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology*; D008564:Membrane Potentials; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism*; D009865:Oocytes; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology; D014981:Xenopus
D017931:DNA Primers; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008012:Lidocaine