Regulation of cardiac gap junctions by protein phosphatases

Hood, Ashleigh R.; Ai, Xun; Pogwizd, Steven M.

doi:10.1016/j.yjmcc.2017.05.002

Cited by 24 publications

(12 citation statements)

References 90 publications

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“…Connexin phosphorylation plays an important role in regulating biological function [ 22 ]. Western blot analysis showed a significant ( p < 0.05) increase in the amount of Cx43 phosphorylated on Ser368 in DOXO-treated mice ( Figure 2 B) after seven days of treatment.…”

Section: Resultsmentioning

confidence: 99%

Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity

Pecoraro

Ciccarelli

Fiordelisi

et al. 2018

IJMS

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Doxorubicin (DOXO) administration induces alterations in Connexin 43 (Cx43) expression and localization, thus, inducing alterations in chemical and electrical signal transmission between cardiomyocytes and in intracellular calcium homeostasis even evident after a single administration. This study was designed to evaluate if Diazoxide (DZX), a specific opener of mitochondrial KATP channels widely used for its cardioprotective effects, can fight DOXO-induced cardiotoxicity in a short-time mouse model. DZX (20 mg/kg i.p.) was administered 30 min before DOXO (10 mg/kg i.p.) in C57BL/6j female mice for 1–3 or seven days once every other day. A recovery of cardiac parameters, evaluated by Echocardiography, were observed in DZX+DOXO co-treated mice. Western blot analysis performed on heart lysates showed an increase in sarco/endoplasmic reticulum Ca2+-ATPase (SERCAII) and a reduction in phospholamban (PLB) amounts in DZX+DOXO co-treated mice. A contemporary recovery of intracellular Ca2+-signal, detected spectrofluorometrically by means of FURA-2AM, was observed in these mice. Cx43 expression and localization, analyzed by Western blot and confirmed by immunofluorescence analysis, showed that DZX co-treatement increases Cx43 amount both on sarcoplasmic membrane and on mitochondria. In conclusion, our data demonstrate that, in a short-time mouse model of DOXO-induced cardiotoxicity, DZX exerts its cardioprotective effects also by enhancing the amount Cx43.

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Section: Resultsmentioning

confidence: 99%

Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity

Pecoraro

Ciccarelli

Fiordelisi

et al. 2018

IJMS

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“…This phosphorylation also induces slower recovery following channel inactivation and increased sodium late current, which results in a prolonged action potential and slower cardiac conduction. Other modifiers of connexin-43 and Na v 1.5 phosphorylation levels include casein kinase 1, MAPKs, Src kinases, and Akt (for a thorough review of PTM via kinases, please see these most recent reviews (Delmar and Liang 2012;Hood et al 2017;Leithe et al 2018;Marionneau and Abriel 2015;Palatinus et al 2012;Rook et al 2012;Lampe 2009, 2018)).…”

Section: Trafficking and Localization Of Electrical Coupling Componentsmentioning

confidence: 99%

At the heart of inter- and intracellular signaling: the intercalated disc

et al. 2018

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Proper cardiac function requires the synchronous mechanical and electrical coupling of individual cardiomyocytes. The intercalated disc (ID) mediates coupling of neighboring myocytes through intercellular signaling. Intercellular communication is highly regulated via intracellular signaling, and signaling pathways originating from the ID control cardiomyocyte remodeling and function. Herein, we present an overview of the inter- and intracellular signaling that occurs at and originates from the intercalated disc in normal physiology and pathophysiology. This review highlights the importance of the intercalated disc as an integrator of signaling events regulating homeostasis and stress responses in the heart and the center of several pathophysiological processes mediating the development of cardiomyopathies.

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“…PKC directly phosphorylates Cx43 at S368 and this phosphorylation reduces the intercellular communication via gap junctions. The role of Cx43 phosphorylation for gap junction dynamics, which is not only controlled by kinases but also by phosphatases [ 29 ], is reviewed in [ 69 ].…”

Section: Introductionmentioning

confidence: 99%

Connexin 43 phosphorylation by casein kinase 1 is essential for the cardioprotection by ischemic preconditioning

et al. 2021

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Myocardial connexin 43 (Cx43) forms gap junctions and hemichannels, and is also present within subsarcolemmal mitochondria. The protein is phosphorylated by several kinases including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and casein kinase 1 (CK1). A reduction in Cx43 content abrogates myocardial infarct size reduction by ischemic preconditioning (IPC). The present study characterizes the contribution of Cx43 phosphorylation towards mitochondrial function, hemichannel activity, and the cardioprotection by IPC in wild-type (WT) mice and in mice in which Cx43-phosphorylation sites targeted by above kinases are mutated to non-phosphorylatable residues (Cx43MAPKmut, Cx43PKCmut, and Cx43CK1mut mice). The amount of Cx43 in the left ventricle and in mitochondria was reduced in all mutant strains compared to WT mice and Cx43 phosphorylation was altered at residues not directly targeted by the mutations. Whereas complex 1 respiration was reduced in all strains, complex 2 respiration was decreased in Cx43CK1mut mice only. In Cx43 epitope-mutated mice, formation of reactive oxygen species and opening of the mitochondrial permeability transition pore were not affected. The hemichannel open probability was reduced in Cx43PKCmut and Cx43CK1mut but not in Cx43MAPKmut cardiomyocytes. Infarct size in isolated saline-perfused hearts after ischemia/reperfusion (45 min/120 min) was comparable between genotypes and was significantly reduced by IPC (3 × 3 min ischemia/5 min reperfusion) in WT, Cx43MAPKmut, and Cx43PKCmut, but not in Cx43CK1mut mice, an effect independent from the amount of Cx43 and the probability of hemichannel opening. Taken together, our study shows that alterations of Cx43 phosphorylation affect specific cellular functions and highlights the importance of Cx43 phosphorylation by CK1 for IPC’s cardioprotection.

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Regulation of cardiac gap junctions by protein phosphatases

Cited by 24 publications

References 90 publications

Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity

Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity

At the heart of inter- and intracellular signaling: the intercalated disc

Connexin 43 phosphorylation by casein kinase 1 is essential for the cardioprotection by ischemic preconditioning

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