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Computational Analysis in Ion Channelopathies

Flecainide sensitivity of a Na channel long QT mutation shows an open-channel blocking mechanism for use-dependent block

¹Department of Medicine and Center for Cardiovascular Research and ²Department of Physiology and Biophysics, University of Illinois at Chicago; and ³Department of Medicine, University of Chicago, Chicago, Illinois

Submitted 14 December 2005 ; accepted in final form 20 February 2006

A long QT mutation in the cardiac sodium channel, D1790G (DG), shows enhanced flecainide use-dependent block (UDB). The relative importance of open and inactivated states of the channel in flecainide UDB has been controversial. We used a modifiable, inactivation-deficient mutant channel that contains the F1486C mutation in the IFM motif to investigate the UDB difference between the wild-type (WT-ICM) and DG (DG-ICM) channels. UDB at 5 Hz was greater in DG-ICM than WT-ICM, and IC₅₀ values for steady-state UDB were 7.19 and 18.06 µM, respectively. When [2-(trimethyammonium) ethyl]methanethiosulfonate bromide (MTSET) was included in the pipette and fast inactivation was disabled, IC₅₀ was 5.04 µM for DG-ICM and 12.63 µM for WT-ICM. We measured open-channel block by flecainide directly in MTSET-treated, noninactivating ICM channels. Steady-state block was higher for DG-ICM than WT-ICM (IC₅₀ was 2.34 µM for DG-ICM and 5.87 µM for WT-ICM), suggesting that open-channel block is an important determinant of flecainide UDB. We obtained association (k_on) and dissociation (k_off) rates for open-channel block by the Langmuir-isotherm model. They were k_off = 31.37 s^–1, k_on = 5.83 s^–1·µM^–1, and calculated K_d = 5.38 µM for WT-ICM (where K_d = k_off/k_on); and k_off = 24.88 s^–1, k_on = 9.54 s^–1·µM^–1, and calculated K_d = 2.61 µM for DG-ICM. These K_d values were similar to IC₅₀ measured from steady-state open-channel block. Furthermore, we modeled UDB mathematically by using these kinetic rates and found that the model predicted experimental UDB accurately. The recovery from UDB had a minor contribution to UDB. Flecainide UDB is predominantly determined by an open-channel blocking mechanism, and DG-ICM channels appeared to have an altered open-channel state with higher flecainide affinity than WT-ICM.

sodium channel; long QT syndrome; electrophysiology