Cx43 phosphorylation–mediated effects on ERK and Akt protect against ischemia reperfusion injury and alter the stability of the stress-inducible protein NDRG1

Solan, Joell L.; Márquez-Rosado, Lucrecia; Lampe, Paul D.

doi:10.1074/jbc.ra119.009162

Cited by 25 publications

(34 citation statements)

References 62 publications

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“…The analysis of the amount of Cx43 in this strain in vascular smooth muscle cells did not demonstrate reduced levels of Cx43, which may be due to the different tissue/cell types analyzed [ 34 ]. In Cx43 PKCmut and Cx43 CK1mut mice, we found a similar decrease of Cx43 in mouse hearts as previously published [ 30 , 54 , 70 ]. Whereas others suggested that the decreased Cx43 protein levels in Cx43 CK1mut mice are due to posttranscriptional alterations [ 70 ], the reason for the reduced Cx43 protein amount in Cx43 MAPKmut , Cx43 PKCmut , and Cx43 CK1mut mice remains unclear.…”

Section: Discussionsupporting

confidence: 90%

“…However, the similar infarct sizes following I/R we observed in all strains analyzed argue against an influence of Cx43 phosphorylation at MAPK, PKC, or CK1 target sites on myocardial I/R injury per se. Similar infarct sizes in WT and Cx43 CK1mut mice have already been demonstrated after myocardial I/R in animals less than 1 year old [70]. However, it must be considered that in the analyzed mouse strains-especially in Cx43 PKCmut mice-not only the phosphorylation of Cx43 but also the total amount of the protein is reduced.…”

Section: Cx43supporting

confidence: 63%

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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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Section: Discussionsupporting

confidence: 90%

Section: Cx43supporting

confidence: 63%

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

et al. 2021

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“…Cx43 CK1 mice develop deleterious cardiac phenotypes (Remo et al, 2011) and differ in their response to ischemia reperfusion injury (Solan et al, 2019) owing to alterations in cardiac gap junction formation and function, lending support to the importance of these phosphorylation sites during the injury response. In the latter case, increased phosphorylation of Cx43 at MAPK sites S262, S279 and S282 was observed in cardiac tissue in the Cx43 CK1 mice (Solan et al, 2019). Interestingly, Cx43 MAPK mice closed wounds ∼20% faster than Cx43 WT .…”

Section: Resultsmentioning

confidence: 94%

“…For example, in the normal mouse heart, Cx43 is heavily phosphorylated at CK1 sites, but upon ischemia, these sites rapidly become dephosphorylated followed by gap junction disassembly (Axelsen et al, 2006;Lampe et al, 2006). Cx43 CK1 mice develop deleterious cardiac phenotypes (Remo et al, 2011) and differ in their response to ischemia reperfusion injury (Solan et al, 2019) owing to alterations in cardiac gap junction formation and function, lending support to the importance of these phosphorylation sites during the injury response. In the latter case, increased phosphorylation of Cx43 at MAPK sites S262, S279 and S282 was observed in cardiac tissue in the Cx43 CK1 mice (Solan et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of connexin 43 at MAPK, PKC or CK1 sites each distinctly alter the kinetics of epidermal wound repair

Lastwika

Dunn

Solan

et al. 2019

Journal of Cell Science

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The gap junction protein connexin 43 (Cx43) is a key player in wound healing, and inhibitors of Cx43, which speed epidermal wound healing, are currently in clinical trials. Here, we provide direct in vivo evidence that specific phosphorylation events on Cx43 change the physiological response during wound healing. Blocking phosphorylation, through mutation of serine residues in Cx43 at the protein kinase C (PKC) or casein kinase 1 (CK1) sites, significantly slowed the rate of wound closure in vivo and in vitro and resulted in a thicker epidermal layer after reepithelialization. Conversely, preventing Cx43 phosphorylation by mitogen-activated protein kinases (MAPKs) through mutation significantly increased the rate of wound closure in vivo. Defects in migration, but not proliferation, in all mutants were partially rescued in vitro by changing serine residues to aspartic or glutamic acid. These data prove that specific Cx43 phosphorylation events play an important role at different stages of wound healing. Thus, a clear physiological understanding of the spatiotemporal regulation of kinase activation and consequent effects on gap junctions could lead to a more targeted approach to modulating Cx43 expression during wound healing.

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“…ERK1/2 is involved in the reperfusion injury salvage kinase (RISK) pathway, which confers cardioprotection when activated (32,33). The activation of ERK1/2 signaling protects the heart from ischemia reperfusion injury (34,35). However, in aging hearts, the activation of ERK1/2 is compromised, which leads to the impairment of cardiac tolerance to ischemia.…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of ERK1/2 signaling protects against myocardial ischemia via inhibition of mitochondrial fragmentation in the aging heart

et al. 2021

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Background: Studies have shown that the ability of the myocardium to tolerate ischemia becomes significantly compromised with age. During ischemia, several endogenous protective signals are activated to protect the heart from injury, among which extracellular-signal regulated kinase (ERK) 1/2 signaling has been established as playing a pivotal role. However, in aging hearts, the activation of ERK1/2 is compromised. Mitogen-activated protein kinase/ERK kinase (MEK) is a major regulator of ERK1/2 signaling. In the present study, we investigated whether transduction of CaMEK, a constitutively activated MEK, using adeno-associated virus serotype 9 (AAV9) could protect the aging heart against ischemia.Methods: Myocardial ischemia models were established in aging mice and senescent cardiomyocytes, and AAV9-mediated delivery of CaMEK was applied. Echocardiography, fluorescent staining, transmission electron microscopy, flow cytometry, and immunoblotting were used to explore the effects of CaMEK and their underlying mechanism.Results: AAV9-CaMEK activated ERK1/2 signaling and exerted cardioprotective effects against ischemia in aging hearts. Specifically, CaMEK transduction decreased dynamin-related protein-1 (Drp1) expression and phosphorylation at serine 616, resulting in improved mitochondrial morphology and function in aging ischemic hearts. Furthermore, CaMEK transduction exerted similar protective effects in senescent cardiomyocytes under hypoxia. Meanwhile, with the inhibition of ERK1/2 signaling in senescent cardiomyocytes under hypoxia, the opposite effects were observed, including an increase in mitochondrial fragmentation and aggravation of mitochondrial dysfunction and cell apoptosis. Conclusions:Our results suggested that AAV9-CaMEK alleviated ischemia-induced myocardium injury in the aging heart, at least in part, through inhibition of mitochondrial fragmentation. Therefore, AAV9-CaMEK is a potential intervention for prevention of ischemia-induced injury of the aging myocardium.

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Cx43 phosphorylation–mediated effects on ERK and Akt protect against ischemia reperfusion injury and alter the stability of the stress-inducible protein NDRG1

Cited by 25 publications

References 62 publications

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

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

Phosphorylation of connexin 43 at MAPK, PKC or CK1 sites each distinctly alter the kinetics of epidermal wound repair

Constitutive activation of ERK1/2 signaling protects against myocardial ischemia via inhibition of mitochondrial fragmentation in the aging heart

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