PMID- 31865383
OWN - NLM
STAT- MEDLINE
DCOM- 20210611
LR  - 20240202
IS  - 1540-7748 (Electronic)
IS  - 0022-1295 (Print)
IS  - 0022-1295 (Linking)
VI  - 152
IP  - 2
DP  - 2020 Feb 3
TI  - An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of 
      inactivation by CaM and FHF.
LID - 10.1085/jgp.201912434 [doi]
LID - e201912434
AB  - Voltage gated sodium channel (VGSC) activation drives the action potential 
      upstroke in cardiac myocytes, skeletal muscles, and neurons. After opening, VGSCs 
      rapidly enter a non-conducting, inactivated state. Impaired inactivation causes 
      persistent inward current and underlies cardiac arrhythmias. VGSC auxiliary 
      proteins calmodulin (CaM) and fibroblast growth factor homologous factors (FHFs) 
      bind to the channel's C-terminal domain (CTD) and limit pathogenic persistent 
      currents. The structural details and mechanisms mediating these effects are not 
      clear. Building on recently published cryo-EM structures, we show that CaM and 
      FHF limit persistent currents in the cardiac NaV1.5 VGSC by stabilizing an 
      interaction between the channel's CTD and III-IV linker region. Perturbation of 
      this intramolecular interaction increases persistent current and shifts the 
      voltage dependence of steady-state inactivation. Interestingly, the NaV1.5 
      residues involved in the interaction are sites mutated in the arrhythmogenic long 
      QT3 syndrome (LQT3). Along with electrophysiological investigations of this 
      interaction, we present structural models that suggest how CaM and FHF stabilize 
      the interaction and thereby limit the persistent current. The critical residues 
      at the interaction site are conserved among VGSC isoforms, and subtle 
      substitutions provide an explanation for differences in inactivation among the 
      isoforms.
CI  - (c) 2019 Gade et al.
FAU - Gade, Aravind R
AU  - Gade AR
AD  - Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY.
FAU - Marx, Steven O
AU  - Marx SO
AD  - Division of Cardiology, Department of Medicine, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY.
AD  - Department of Pharmacology, Vagelos College of Physicians and Surgeons, Columbia 
      University, New York, NY.
FAU - Pitt, Geoffrey S
AU  - Pitt GS
AD  - Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY.
LA  - eng
GR  - R01 HL071165/HL/NHLBI NIH HHS/United States
GR  - R01 MH118934/MH/NIMH NIH HHS/United States
GR  - R01 HL122967/HL/NHLBI NIH HHS/United States
GR  - T32 HL160520/HL/NHLBI NIH HHS/United States
GR  - R01 HL112918/HL/NHLBI NIH HHS/United States
GR  - R01 HL140934/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Gen Physiol
JT  - The Journal of general physiology
JID - 2985110R
RN  - 0 (Calmodulin)
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 0 (Protein Isoforms)
RN  - 0 (SCN5A protein, human)
RN  - 62031-54-3 (Fibroblast Growth Factors)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Action Potentials/physiology
MH  - Arrhythmias, Cardiac/metabolism
MH  - Binding Sites/physiology
MH  - Calcium/metabolism
MH  - Calmodulin/*metabolism
MH  - Cell Line
MH  - Fibroblast Growth Factors/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Mutation/genetics
MH  - NAV1.5 Voltage-Gated Sodium Channel/*metabolism
MH  - Neurons/metabolism
MH  - Patch-Clamp Techniques/methods
MH  - Protein Binding/physiology
MH  - Protein Isoforms/metabolism
PMC - PMC7062510
EDAT- 2019/12/23 06:00
MHDA- 2021/06/12 06:00
PMCR- 2020/08/03
CRDT- 2019/12/23 06:00
PHST- 2019/07/01 00:00 [received]
PHST- 2019/11/25 00:00 [accepted]
PHST- 2019/12/23 06:00 [entrez]
PHST- 2019/12/23 06:00 [pubmed]
PHST- 2021/06/12 06:00 [medline]
PHST- 2020/08/03 00:00 [pmc-release]
AID - 133475 [pii]
AID - 201912434 [pii]
AID - 10.1085/jgp.201912434 [doi]
PST - ppublish
SO  - J Gen Physiol. 2020 Feb 3;152(2):e201912434. doi: 10.1085/jgp.201912434.