Cx43 Channel Gating and Permeation: Multiple Phosphorylation-Dependent Roles of the Carboxyl Terminus
AffiliationUniv Arizona, Dept Physiol
MetadataShow full item record
CitationEk-Vitorín JF, Pontifex TK, Burt JM. Cx43 Channel Gating and Permeation: Multiple Phosphorylation-Dependent Roles of the Carboxyl Terminus. International Journal of Molecular Sciences. 2018; 19(6):1659.
Rights© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractConnexin 43 (Cx43), a gap junction protein seemingly fit to support cardiac impulse propagation and synchronic contraction, is phosphorylated in normoxia by casein kinase 1 (CK1). However, during cardiac ischemia or pressure overload hypertrophy, this phosphorylation fades, Cx43 abundance decreases at intercalated disks and increases at myocytes' lateral borders, and the risk of arrhythmia rises. Studies in wild-type and transgenic mice indicate that enhanced CK1-phosphorylation of Cx43 protects from arrhythmia, while dephosphorylation precedes arrhythmia vulnerability. The mechanistic bases of these Cx43 (de)phosphoform-linked cardiac phenotypes are unknown. We used patch-clamp and dye injection techniques to study the channel function (gating, permeability) of Cx43 mutants wherein CK1-targeted serines were replaced by aspartate (Cx43-CK1-D) or alanine (Cx43-CK1-A) to emulate phosphorylation and dephosphorylation, respectively. Cx43-CK1-D, but not Cx43-CK1-A, displayed high Voltage-sensitivity and variable permselectivity. Both mutants showed multiple channel open states with overall increased conductivity, resistance to acidification-induced junctional uncoupling, and hemichannel openings in normal external calcium. Modest differences in the mutant channels' function and regulation imply the involvement of dissimilar structural conformations of the interacting domains of Cx43 in electrical and chemical gating that may contribute to the divergent phenotypes of CK1-(de)phospho-mimicking Cx43 transgenic mice and that may bear significance in arrhythmogenesis.
NoteOpen Access Journal.
VersionFinal published version
SponsorsNational Institutes of Health (Heart, Lung and Blood Institute) [HL058732, HL131712]
Except where otherwise noted, this item's license is described as © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
- Casein kinase 1 regulates connexin-43 gap junction assembly.
- Authors: Cooper CD, Lampe PD
- Issue date: 2002 Nov 22
- Connexin 43 phosphorylation by casein kinase 1 is essential for the cardioprotection by ischemic preconditioning.
- Authors: Hirschhäuser C, Lissoni A, Görge PM, Lampe PD, Heger J, Schlüter KD, Leybaert L, Schulz R, Boengler K
- Issue date: 2021 Mar 22
- Determinants of Cx43 Channel Gating and Permeation: The Amino Terminus.
- Authors: Ek Vitorín JF, Pontifex TK, Burt JM
- Issue date: 2016 Jan 5
- Cx43 phosphorylation-mediated effects on ERK and Akt protect against ischemia reperfusion injury and alter the stability of the stress-inducible protein NDRG1.
- Authors: Solan JL, Márquez-Rosado L, Lampe PD
- Issue date: 2019 Aug 2
- Emerging issues of connexin channels: biophysics fills the gap.
- Authors: Harris AL
- Issue date: 2001 Aug