PMID- 34806324
OWN - NLM
STAT- MEDLINE
DCOM- 20220316
LR  - 20240404
IS  - 2051-817X (Electronic)
IS  - 2051-817X (Linking)
VI  - 9
IP  - 22
DP  - 2021 Nov
TI  - Phosphorylation of Lamin A/C at serine 22 modulates Na(v) 1.5 function.
PG  - e15121
LID - 10.14814/phy2.15121 [doi]
LID - e15121
AB  - Variants in the LMNA gene, which encodes for Lamin A/C, are associated with 
      cardiac conduction disease (CCD). We previously reported that Lamin A/C variants 
      p.R545H and p.A287Lfs*193, which were identified in CCD patients, decreased peak 
      I(Na) in HEK-293 cells expressing Na(v) 1.5. Decreased peak I(Na) in the cardiac 
      conduction system could account for patients' atrioventricular block. We found 
      that serine 22 (Ser 22) phosphorylation of Lamin A/C was decreased in the p.R545H 
      variant and hypothesized that lamin phosphorylation modulated Na(v) 1.5 activity. 
      To test this hypothesis, we assessed Na(v) 1.5 function in HEK-293 cells 
      co-transfected with LMNA variants or treated with the small molecule LBL1 
      (lamin-binding ligand 1). LBL1 decreased Ser 22 phosphorylation by 65% but did 
      not affect Na(v) 1.5 function. To test the complete loss of phosphorylation, we 
      generated a version of LMNA with serine 22 converted to alanine 22 (S22A-LMNA); 
      and a version of mutant R545H-LMNA that mimics phosphorylation via serine 22 to 
      aspartic acid 22 substitution (S22D-R545H-LMNA). We found that S22A-LMNA 
      inhibited Lamin-mediated activation of peak I(Na) by 63% and shifted 
      voltage-dependency of steady-state inactivation of Na(v) 1.5. Conversely, 
      S22D-R545H-LMNA abolished the effects of mutant R545H-LMNA on voltage-dependency 
      but not peak I(Na) . We conclude that Lamin A/C Ser 22 phosphorylation can 
      modulate Na(v) 1.5 function and contributes to the mechanism by which R545H-LMNA 
      alters Na(v) 1.5 function. The differential impact of complete versus partial 
      loss of Ser 22 phosphorylation suggests a threshold of phosphorylation that is 
      required for full Na(v) 1.5 modulation. This is the first study to link Lamin A/C 
      phosphorylation to Na(v) 1.5 function.
CI  - (c) 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on 
      behalf of The Physiological Society and the American Physiological Society.
FAU - Olaopa, Michael A
AU  - Olaopa MA
AD  - Department of Chemical Physiology and Biochemistry, Oregon Health & Science 
      University, Portland, Oregon, USA.
AD  - Krannert Institute of Cardiology, Department of Medicine, Indiana University 
      School of Medicine, Indianapolis, Indiana, USA.
FAU - Ai, Tomohiko
AU  - Ai T
AD  - Krannert Institute of Cardiology, Department of Medicine, Indiana University 
      School of Medicine, Indianapolis, Indiana, USA.
AD  - Department of Clinical Laboratory Medicine, Juntendo University, Tokyo, Japan.
FAU - Chao, Bo
AU  - Chao B
AD  - Department of Chemical Physiology and Biochemistry, Oregon Health & Science 
      University, Portland, Oregon, USA.
FAU - Xiao, Xiangshu
AU  - Xiao X
AD  - Department of Chemical Physiology and Biochemistry, Oregon Health & Science 
      University, Portland, Oregon, USA.
FAU - Vatta, Matteo
AU  - Vatta M
AD  - Krannert Institute of Cardiology, Department of Medicine, Indiana University 
      School of Medicine, Indianapolis, Indiana, USA.
FAU - Habecker, Beth A
AU  - Habecker BA
AUID- ORCID: 0000-0002-4658-8730
AD  - Department of Chemical Physiology and Biochemistry, Oregon Health & Science 
      University, Portland, Oregon, USA.
LA  - eng
GR  - R01 CA211866/CA/NCI NIH HHS/United States
GR  - R01 HL093056/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Physiol Rep
JT  - Physiological reports
JID - 101607800
RN  - 0 (LMNA protein, human)
RN  - 0 (Lamin Type A)
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 0 (SCN5A protein, human)
SB  - IM
MH  - Cardiac Conduction System Disease/*genetics/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Lamin Type A/*genetics/metabolism
MH  - Mutation
MH  - Mutation, Missense
MH  - NAV1.5 Voltage-Gated Sodium Channel/*metabolism
MH  - Patch-Clamp Techniques
MH  - Phosphorylation
PMC - PMC8606869
OTO - NOTNLM
OT  - Lamin phosphorylation
OT  - Nav1.5
OT  - cardiac conduction disease
COIS- All authors declare no conflict of interest.
EDAT- 2021/11/23 06:00
MHDA- 2022/03/17 06:00
PMCR- 2021/11/21
CRDT- 2021/11/22 07:22
PHST- 2021/10/29 00:00 [revised]
PHST- 2021/07/02 00:00 [received]
PHST- 2021/10/31 00:00 [accepted]
PHST- 2021/11/22 07:22 [entrez]
PHST- 2021/11/23 06:00 [pubmed]
PHST- 2022/03/17 06:00 [medline]
PHST- 2021/11/21 00:00 [pmc-release]
AID - PHY215121 [pii]
AID - 10.14814/phy2.15121 [doi]
PST - ppublish
SO  - Physiol Rep. 2021 Nov;9(22):e15121. doi: 10.14814/phy2.15121.