PMID- 32569350
OWN - NLM
STAT- MEDLINE
DCOM- 20210902
LR  - 20210902
IS  - 1540-7748 (Electronic)
IS  - 0022-1295 (Print)
IS  - 0022-1295 (Linking)
VI  - 152
IP  - 9
DP  - 2020 Sep 7
TI  - E1784K, the most common Brugada syndrome and long-QT syndrome type 3 mutant, 
      disrupts sodium channel inactivation through two separate mechanisms.
LID - 10.1085/jgp.202012595 [doi]
LID - e202012595
AB  - 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.
CI  - (c) 2020 Peters et al.
FAU - Peters, Colin H
AU  - Peters CH
AD  - Department of Physiology and Biophysics, University of Colorado Anschutz Medical 
      Campus, Aurora, CO.
FAU - Watkins, Abeline R
AU  - Watkins AR
AD  - Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 
      Burnaby, BC, Canada.
FAU - Poirier, Olivia L
AU  - Poirier OL
AD  - Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 
      Burnaby, BC, Canada.
FAU - Ruben, Peter C
AU  - Ruben PC
AD  - Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 
      Burnaby, BC, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Gen Physiol
JT  - The Journal of general physiology
JID - 2985110R
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
SB  - IM
MH  - *Brugada Syndrome/genetics
MH  - Humans
MH  - *Long QT Syndrome/genetics
MH  - Mutation
MH  - *NAV1.5 Voltage-Gated Sodium Channel/genetics
PMC - PMC7478868
EDAT- 2020/06/23 06:00
MHDA- 2021/09/03 06:00
PMCR- 2021/03/07
CRDT- 2020/06/23 06:00
PHST- 2020/02/20 00:00 [received]
PHST- 2020/05/29 00:00 [accepted]
PHST- 2020/06/23 06:00 [entrez]
PHST- 2020/06/23 06:00 [pubmed]
PHST- 2021/09/03 06:00 [medline]
PHST- 2021/03/07 00:00 [pmc-release]
AID - 151877 [pii]
AID - jgp.202012595 [pii]
AID - 10.1085/jgp.202012595 [doi]
PST - ppublish
SO  - J Gen Physiol. 2020 Sep 7;152(9):e202012595. doi: 10.1085/jgp.202012595.