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Unexpected Mexiletine Responses of a Mutant Cardiac Na⁺ Channel Implicate the Selectivity Filter as a Structural Determinant of Antiarrhythmic Drug Access

Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan (K.S., N.M., N.S., H.Y., A.Kit.); Departments of Clinical Pharmacology (A.S.), Molecular Pathogenesis (A.Kim.), and Cardiovascular Diseases (M.H.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan (H.S.); and Department of Physiology, Sapporo Medical University, Sapporo, Japan (N.T.)

Gating properties of Na⁺ channels are the critical determinants for the state-dependent block by class I antiarrhythmic drugs; however, recent site-directed mutagenesis studies have shown that the Na⁺ channel selectivity filter region controls drug access to and dissociation from the binding site. To validate these observations, we have exploited a naturally occurring cardiac Na⁺ channel mutation, S1710L, located next to the putative selectivity filter residue of domain 4, and evaluated the pharmacological properties to mexiletine using whole-cell, patch-clamp recordings. Consistent with the large negative shift of steady-state inactivation and the enhanced slow inactivation, the S1710L channel showed greater mexiletine tonic block than wild-type (WT) channel. In contradiction, S1710L showed attenuated use-dependent block by mexiletine and accelerated recovery from block, suggesting that the drug escape though the external access path is facilitated. Extracellularly applied QX-314, a membrane-impermeant derivative of lidocaine, elicited significantly enhanced tonic block in S1710L similar to mexiletine. However, recovery from internally applied QX-314 was accelerated by 4.4-fold in S1710L compared with WT. These results suggest that the drug access to and dissociation from the binding site through the hydrophilic path are substantially altered. Moreover, K⁺ permeability was 1.9-fold increased in S1710L, verifying that the mutated residue is located in the ion-conducting pore. We propose that the Na⁺ channel selectivity filter region is a structural determinant for the antiarrhythmic drug sensitivity in addition to gating properties of the indigenous Na⁺ channels that govern the state-dependent drug block.

Address correspondence to: Dr. Naomasa Makita, Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-8638, Japan. E-mail: makitan{at}med.hokudai.ac.jp

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