RT Journal Article SR Electronic T1 Unexpected Mexiletine Responses of a Mutant Cardiac Na+ Channel Implicate the Selectivity Filter as a Structural Determinant of Antiarrhythmic Drug Access JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 330 OP 336 DO 10.1124/mol.66.2.330 VO 66 IS 2 A1 Sasaki, Koji A1 Makita, Naomasa A1 Sunami, Akihiko A1 Sakurada, Harumizu A1 Shirai, Nobumasa A1 Yokoi, Hisataka A1 Kimura, Akinori A1 Tohse, Noritsugu A1 Hiraoka, Masayasu A1 Kitabatake, Akira YR 2004 UL http://molpharm.aspetjournals.org/content/66/2/330.abstract AB 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.