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E1784K, the most common Brugada syndrome and long-QT syndrome type 3 mutant, disrupts sodium channel inactivation through two separate mechanisms
Copyright policy )E1784K, the most common Brugada syndrome and long-QT syndrome type 3 mutant, disrupts sodium channel inactivation through two separate mechanisms
Inheritable and de novo variants in the cardiac voltage-gated sodium channel, Nav1.5, are responsible for both long-QT syndrome type 3 (LQT3) and Brugada syndrome type 1 (BrS1). Interestingly, a subset of Nav1.5 variants can cause both LQT3 and BrS1. Many of these variants are found in channel structures that form the channel fast inactivation machinery, altering the rate, voltage dependence, and completeness of the fast inactivation process. We used a series of mutants at position 1784 to show that the most common inheritable Nav1.5 variant, E1784K, alters fast inactivation through two separable mechanisms: (1) a charge-dependent interaction that increases the noninactivating current characteristic of E1784K; and (2) a hyperpolarized voltage dependence and accelerated rate of fast inactivation that decreases the peak sodium current. Using a homology model built on the NavPaS structure, we find that the charge-dependent interaction is between E1784 and K1493 in the DIII–DIV linker of the channel, five residues downstream of the putative inactivation gate. This interaction can be disrupted by a positive charge at position 1784 and rescued with the K1493E/E1784K double mutant that abolishes the noninactivating current. However, the double mutant does not restore either the voltage dependence or rates of fast inactivation. Conversely, a mutant at the bottom of DIVS4, K1641D, causes a hyperpolarizing shift in the voltage dependence of fast inactivation and accelerates the rate of fast inactivation without causing an increase in noninactivating current. These findings provide novel mechanistic insights into how the most common inheritable arrhythmogenic mixed syndrome variant, E1784K, simultaneously decreases transient sodium currents and increases noninactivating currents, leading to both BrS1 and LQT3.
Inheritable and de novo variants of voltage-gated sodium channels that lead to sudden cardiac death can affect several different aspects of channel function, making pharmaceutical treatment difficult. Peters et al. show that the E1784K mutant in Nav1.5 alters channel function through two distinct and separable mechanisms.
- Simon Fraser University Canada
- University of Colorado Anschutz Medical Campus United States
Microsoft Academic Graph classification: Sodium Long QT syndrome Mutant chemistry.chemical_element medicine Voltage dependence Brugada syndrome Sodium channel Depolarization medicine.disease Long QT syndrome type 3 chemistry Biophysics
Physiology, Biophysics, Article, NAV1.5 Voltage-Gated Sodium Channel, Humans, Brugada Syndrome, Long QT Syndrome, Mutation
Physiology, Biophysics, Article, NAV1.5 Voltage-Gated Sodium Channel, Humans, Brugada Syndrome, Long QT Syndrome, Mutation
Microsoft Academic Graph classification: Sodium Long QT syndrome Mutant chemistry.chemical_element medicine Voltage dependence Brugada syndrome Sodium channel Depolarization medicine.disease Long QT syndrome type 3 chemistry Biophysics
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- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Simon Fraser University Canada
- University of Colorado Anschutz Medical Campus United States
Inheritable and de novo variants in the cardiac voltage-gated sodium channel, Nav1.5, are responsible for both long-QT syndrome type 3 (LQT3) and Brugada syndrome type 1 (BrS1). Interestingly, a subset of Nav1.5 variants can cause both LQT3 and BrS1. Many of these variants are found in channel structures that form the channel fast inactivation machinery, altering the rate, voltage dependence, and completeness of the fast inactivation process. We used a series of mutants at position 1784 to show that the most common inheritable Nav1.5 variant, E1784K, alters fast inactivation through two separable mechanisms: (1) a charge-dependent interaction that increases the noninactivating current characteristic of E1784K; and (2) a hyperpolarized voltage dependence and accelerated rate of fast inactivation that decreases the peak sodium current. Using a homology model built on the NavPaS structure, we find that the charge-dependent interaction is between E1784 and K1493 in the DIII–DIV linker of the channel, five residues downstream of the putative inactivation gate. This interaction can be disrupted by a positive charge at position 1784 and rescued with the K1493E/E1784K double mutant that abolishes the noninactivating current. However, the double mutant does not restore either the voltage dependence or rates of fast inactivation. Conversely, a mutant at the bottom of DIVS4, K1641D, causes a hyperpolarizing shift in the voltage dependence of fast inactivation and accelerates the rate of fast inactivation without causing an increase in noninactivating current. These findings provide novel mechanistic insights into how the most common inheritable arrhythmogenic mixed syndrome variant, E1784K, simultaneously decreases transient sodium currents and increases noninactivating currents, leading to both BrS1 and LQT3.
Inheritable and de novo variants of voltage-gated sodium channels that lead to sudden cardiac death can affect several different aspects of channel function, making pharmaceutical treatment difficult. Peters et al. show that the E1784K mutant in Nav1.5 alters channel function through two distinct and separable mechanisms.