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Regulation of gap junction conductance by calcineurin through Cx43 phosphorylation: implications for action potential conduction

Jabr, R, Hatch,, FS, Salvage, SC, Orlowski, A, Lampe, PD and Fry, CH (2016) Regulation of gap junction conductance by calcineurin through Cx43 phosphorylation: implications for action potential conduction Pfluegers Archiv: European journal of physiology.

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Abstract

Cardiac arrhythmias are associated with raised intracellular [Ca2+] and slowed action potential conduction caused by reduced gap junction (GJ) electrical conductance (Gj). Ventricular GJs are composed of connexin proteins (Cx43), with Gj determined by Cx43 phosphorylation status. Connexin phosphorylation is an interplay between protein kinases and phosphatases but the precise pathways are unknown. We aimed to identify key Ca2+-dependent phosphorylation sites on Cx43 that regulate cardiac gap junction conductance and action potential conduction velocity. We investigated the role of the Ca2+-dependent phosphatase, calcineurin. Intracellular [Ca2+] was raised in guinea-pig myocardium by a low-Na solution or increased stimulation. Conduction velocity and Gj were measured in multicellular strips. Phosphorylation of Cx43 serine residues (S365 and S368) and of the intermediary regulator I1 at threonine35 was measured by Western blot. Measurements were made in the presence and absence of inhibitors to calcineurin, I1 or protein phosphatase-1 and phosphatase-2. Raised [Ca2+]i decreased Gj, reduced Cx43 phosphorylation at S365 and increased it at S368; these changes were reversed by calcineurin inhibitors. Cx43-S368 phosphorylation was reversed by the protein kinase C inhibitor chelerythrine. Raised [Ca2+]i also decreased I1 phosphorylation, also prevented by calcineurin inhibitors, to increase activity of the Ca2+-independent phosphatase, PPI. The PP1 inhibitor, tautomycin, prevented Cx43-365 dephosphorylation, Cx43-S368 phosphorylation and Gj reduction in raised [Ca2+]i. PP2A had no role. Conduction velocity was reduced by raised [Ca2+]i and reversed by calcineurin inhibitors. Reduced action potential conduction and Gj in raised [Ca2+] are regulated by calcineurin-dependent Cx43-S365 phosphorylation, leading to Cx43-S368 dephosphorylation. The calcineurin action is indirect, via I1 dephosphorylation and subsequent activation of PP1.

Item Type: Article
Subjects : Biosciences
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
AuthorsEmailORCID
Jabr, RUNSPECIFIEDUNSPECIFIED
Hatch,, FSUNSPECIFIEDUNSPECIFIED
Salvage, SCUNSPECIFIEDUNSPECIFIED
Orlowski, AUNSPECIFIEDUNSPECIFIED
Lampe, PDUNSPECIFIEDUNSPECIFIED
Fry, CHUNSPECIFIEDUNSPECIFIED
Date : 19 October 2016
Identification Number : https://doi.org/10.1007/s00424-016-1885-7
Copyright Disclaimer : © The Author(s) 2016 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Depositing User : Symplectic Elements
Date Deposited : 25 Oct 2016 14:49
Last Modified : 25 Oct 2016 14:49
URI: http://epubs.surrey.ac.uk/id/eprint/812603

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