PT  - JOURNAL ARTICLE
AU  - Sasaki, Koji
AU  - Makita, Naomasa
AU  - Sunami, Akihiko
AU  - Sakurada, Harumizu
AU  - Shirai, Nobumasa
AU  - Yokoi, Hisataka
AU  - Kimura, Akinori
AU  - Tohse, Noritsugu
AU  - Hiraoka, Masayasu
AU  - Kitabatake, Akira
TI  - Unexpected Mexiletine Responses of a Mutant Cardiac Na<sup>+</sup> Channel Implicate the Selectivity Filter as a Structural Determinant of Antiarrhythmic Drug Access
AID  - 10.1124/mol.66.2.330
DP  - 2004 Aug 01
TA  - Molecular Pharmacology
PG  - 330--336
VI  - 66
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/66/2/330.short
4100  - http://molpharm.aspetjournals.org/content/66/2/330.full
SO  - Mol Pharmacol2004 Aug 01; 66
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.