PMID- 37191672
OWN - NLM
STAT- MEDLINE
DCOM- 20230518
LR  - 20231117
IS  - 1540-7748 (Electronic)
IS  - 0022-1295 (Print)
IS  - 0022-1295 (Linking)
VI  - 155
IP  - 7
DP  - 2023 Jul 3
TI  - Remodeled connexin 43 hemichannels alter cardiac excitability and promote 
      arrhythmias.
LID - 10.1085/jgp.202213150 [doi]
LID - e202213150
AB  - Connexin-43 (Cx43) is the most abundant protein forming gap junction channels 
      (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including 
      hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the 
      intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been 
      long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which 
      arrhythmias develop are still debated. Using a model of dystrophic 
      cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant 
      hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, 
      consequently, promote arrhythmias. Here, we aim to evaluate if opening of 
      remodeled Cx43 can serve as a general mechanism to alter cardiac excitability 
      independent of cellular dysfunction associated with a particular cardiomyopathy. 
      To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) 
      that promotes cardiac remodeling of Cx43 protein without apparent cardiac 
      dysfunction. Importantly, when S3A mice were subjected to cardiac stress using 
      the beta-adrenergic agonist isoproterenol (Iso), they displayed acute and severe 
      arrhythmias, which were not observed in WT mice. Pretreatment of S3A mice with 
      the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal 
      electrocardiographic behavior. At the cellular level, when compared with WT, 
      Iso-treated S3A cardiomyocytes showed increased membrane permeability, greater 
      plasma membrane depolarization, and Ca2+ overload, which likely caused prolonged 
      action potentials, delayed after depolarizations, and triggered activity. All 
      these cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our 
      results support the notion that opening of remodeled Cx43 hemichannels, 
      regardless of the type of cardiomyopathy, is sufficient to mediate 
      cardiac-stress-induced arrhythmogenicity.
CI  - (c) 2023 Lillo et al.
FAU - Lillo, Mauricio A
AU  - Lillo MA
AUID- ORCID: 0000-0002-2823-6619
AD  - Department of Pharmacology, Physiology and Neuroscience, Rutgers University, New 
      Jersey Medical School, Newark, NJ, USA.
FAU - Munoz, Manuel
AU  - Munoz M
AUID- ORCID: 0000-0001-7024-9600
AD  - Department of Physiology and Membrane Biology, University of California, Davis. 
      Davis, CA, USA.
FAU - Rhana, Paula
AU  - Rhana P
AUID- ORCID: 0000-0002-6065-2903
AD  - Department of Physiology and Membrane Biology, University of California, Davis. 
      Davis, CA, USA.
FAU - Gaul-Muller, Kelli
AU  - Gaul-Muller K
AUID- ORCID: 0000-0002-1351-6036
AD  - Department of Pharmacology, Physiology and Neuroscience, Rutgers University, New 
      Jersey Medical School, Newark, NJ, USA.
FAU - Quan, Jonathan
AU  - Quan J
AUID- ORCID: 0000-0002-3312-6908
AD  - Department of Physiology and Membrane Biology, University of California, Davis. 
      Davis, CA, USA.
FAU - Shirokova, Natalia
AU  - Shirokova N
AUID- ORCID: 0000-0003-4648-4592
AD  - Department of Pharmacology, Physiology and Neuroscience, Rutgers University, New 
      Jersey Medical School, Newark, NJ, USA.
FAU - Xie, Lai-Hua
AU  - Xie LH
AUID- ORCID: 0000-0003-2600-2269
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University, New Jersey 
      Medical School, Newark, NJ, USA.
FAU - Santana, Luis Fernando
AU  - Santana LF
AUID- ORCID: 0000-0002-4297-8029
AD  - Department of Physiology and Membrane Biology, University of California, Davis. 
      Davis, CA, USA.
FAU - Fraidenraich, Diego
AU  - Fraidenraich D
AUID- ORCID: 0000-0001-5369-4446
AD  - Department of Cell Biology and Molecular Medicine, Rutgers University, New Jersey 
      Medical School, Newark, NJ, USA.
FAU - Contreras, Jorge E
AU  - Contreras JE
AUID- ORCID: 0000-0001-9203-1602
AD  - Department of Pharmacology, Physiology and Neuroscience, Rutgers University, New 
      Jersey Medical School, Newark, NJ, USA.
AD  - Department of Physiology and Membrane Biology, University of California, Davis. 
      Davis, CA, USA.
LA  - eng
GR  - R01 HL157116/HL/NHLBI NIH HHS/United States
GR  - R01 HL133294/HL/NHLBI NIH HHS/United States
GR  - R01 HL141170/HL/NHLBI NIH HHS/United States
GR  - R01 HL093342/HL/NHLBI NIH HHS/United States
GR  - R01 GM099490/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230516
PL  - United States
TA  - J Gen Physiol
JT  - The Journal of general physiology
JID - 2985110R
RN  - 0 (Connexin 43)
RN  - 0 (Ion Channels)
RN  - L628TT009W (Isoproterenol)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Connexin 43/genetics/metabolism
MH  - Myocardium/metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - Arrhythmias, Cardiac/metabolism
MH  - Gap Junctions
MH  - Ion Channels/metabolism
MH  - *Cardiomyopathies
MH  - Isoproterenol
PMC - PMC10192603
COIS- Disclosures: The authors declare no competing interests exist.
EDAT- 2023/05/16 13:09
MHDA- 2023/05/18 06:42
PMCR- 2023/11/16
CRDT- 2023/05/16 11:03
PHST- 2022/03/21 00:00 [received]
PHST- 2023/01/25 00:00 [revised]
PHST- 2023/04/06 00:00 [revised]
PHST- 2023/04/24 00:00 [accepted]
PHST- 2023/05/18 06:42 [medline]
PHST- 2023/05/16 13:09 [pubmed]
PHST- 2023/05/16 11:03 [entrez]
PHST- 2023/11/16 00:00 [pmc-release]
AID - 214114 [pii]
AID - jgp.202213150 [pii]
AID - 10.1085/jgp.202213150 [doi]
PST - ppublish
SO  - J Gen Physiol. 2023 Jul 3;155(7):e202213150. doi: 10.1085/jgp.202213150. Epub 
      2023 May 16.