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State-Dependent Mibefradil Block of Na⁺ Channels

Departments of Neurobiology, Pharmacology, and Physiology (M.M.M.) and Medicine (D.A.H.), University of Chicago, Chicago, Illinois

Mibefradil is a T-type Ca²⁺ channel antagonist with reported cross-reactivity with other classes of ion channels, including K⁺, Cl^-, and Na⁺ channels. Using whole-cell voltage clamp, we examined mibefradil block of four Na⁺ channel isoforms expressed in human embryonic kidney cells: Na_v1.5 (cardiac), Na_v1.4 (skeletal muscle), Na_v1.2 (brain), and Na_v1.7 (peripheral nerve). Mibefradil blocked Na_v1.5 in a use/frequency-dependent manner, indicating preferential binding to states visited during depolarization. Mibefradil blocked currents of all Na⁺ channel isoforms with similar affinity and a dependence on holding potential, and drug off-rate was slowed at depolarized potentials (k_off was 0.024/s at -130 mV and 0.007/s at -100 mV for Na_v1.5). We further probed the interaction of mibefradil with inactivated Na_v1.5 channels. Neither the degree nor the time course of block was dependent on the stimulus duration, which dramatically changed the residency time of channels in the fast-inactivated state. In addition, inhibiting the binding of the fast inactivation lid (Na_v1.5 ICM + MTSET) did not alter mibefradil block, confirming that the drug does not preferentially interact with the fast-inactivated state. We also tested whether mibefradil interacted with slow-inactivated state(s). When selectively applied to channels after inducing slow inactivation with a 60-s pulse to -10 mV, mibefradil (1 µM) produced 45% fractional block in Na_v1.5 and greater block (88%) in an isoform (Na_v1.4) that slow-inactivates more completely. Our results suggest that mibefradil blocks Na⁺ channels in a state-dependent manner that does not depend on fast inactivation but probably involves interaction with one or more slow-inactivated state(s).

Address correspondence to: Dorothy A. Hanck, 5841 S. Maryland Ave, MC 6094, Chicago, IL 60637. E-mail: dhanck{at}uchicago.edu

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