Residual Cx45 and its relationship to Cx43 in murine ventricular myocardium

Bao, Mingwei; Kanter, Evelyn M.; Huang, Richard Y.‐C.; Maxeiner, Stephan; Frank, Marina; Zhang, Yan; Schuessler, Richard B.; Smith, Timothy W.; Townsend, R. Reid; Rohrs, Henry W.; Berthoud, Viviana M.; Willecke, Klaus; Laing, James G.; Yamada, Kathryn A.

doi:10.4161/chan.5.6.18523

Cited by 26 publications

(24 citation statements)

References 65 publications

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“…Interestingly, a recent study (29) has shown that Cx43 forms gap junction plaque with Cx45 but not with Cx40 in HeLa cells, indicating functional intimacy of Cx43 and Cx45. However, Cx45 is expressed at the early stage of heart development and is downregulated after birth (2,3). Thus the present finding regarding Cx45 in H9c2 cells may not be extrapolated to adult hearts in situ.…”

Section: Discussioncontrasting

confidence: 47%

Role of connexin-43 in protective PI3K-Akt-GSK-3β signaling in cardiomyocytes

Ishikawa

Kuno

Tanno

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Sarcolemmal connexin-43 (Cx43) and mitochondrial Cx43 play distinct roles: formation of gap junctions and production of reactive oxygen species (ROS) for redox signaling. In this study, we examined the hypothesis that Cx43 contributes to activation of a major cytoprotective signal pathway, phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3β (GSK-3β) signaling, in cardiomyocytes. A δ-opioid receptor agonist {[d-Ala(2),d-Leu(5)]enkephalin acetate (DADLE)}, endothelin-1 (ET-1), and insulin-like growth factor-1 (IGF-1) induced phosphorylation of Akt and GSK-3β in H9c2 cardiomyocytes. Reduction of Cx43 protein to 20% of the normal level by Cx43 small interfering RNA abolished phosphorylation of Akt and GSK-3β induced by DADLE or ET-1 but not that induced by IGF-1. DADLE and IGF-1 protected H9c2 cells from necrosis after treatment with H(2)O(2) or antimycin A. The protection by DADLE or ET-1, but not that by IGF-1, was lost by reduction of Cx43 protein expression. In contrast to Akt and GSK-3β, PKC-ε, ERK and p38 mitogen-activated protein kinase were phosphorylated by ET-1 in Cx43-knocked-down cells. Like diazoxide, an activator of the mitochondrial ATP-sensitive K(+) channel, DADLE and ET-1 induced significant ROS production in mitochondria, although such an effect was not observed for IGF-1. Cx43 knockdown did not attenuate the mitochondrial ROS production by DADLE or ET-1. Cx43 was coimmunoprecipitated with the β-subunit of G protein (Gβ), and knockdown of Gβ mimicked the effect of Cx43 knockdown on ET-1-induced phosphorylation of Akt and GSK-3β. These results suggest that Cx43 contributes to activation of class I(B) PI3K in PI3K-Akt-GSK-3β signaling possibly as a cofactor of Gβ in cardiomyocytes.

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Section: Discussioncontrasting

confidence: 47%

Role of connexin-43 in protective PI3K-Akt-GSK-3β signaling in cardiomyocytes

Ishikawa

Kuno

Tanno

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…Connexin45, a far less abundant cardiac connexin [45], can form hetero-typic gap junctions with Cx43, acting in a dominant fashion to disrupt conductance. It is therefore of note that the relative ratio of Cx45/Cx43 was increased in the CRT-TG mice, suggesting increased incidence of heterotypic Cx43/45 channels, and therefore increased gap junction dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Calreticulin Induces Dilated Cardiomyopathy

et al. 2013

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BackgroundCalreticulin, a Ca2+-buffering chaperone of the endoplasmic reticulum, is highly expressed in the embryonic heart and is essential for cardiac development. After birth, the calreticulin gene is sharply down regulated in the heart, and thus, adult hearts have negligible levels of calreticulin. In this study we tested the role of calreticulin in the adult heart.Methodology/Principal FindingsWe generated an inducible transgenic mouse in which calreticulin is targeted to the cardiac tissue using a Cre/loxP system and can be up-regulated in adult hearts. Echocardiography analysis of hearts from transgenic mice expressing calreticulin revealed impaired left ventricular systolic and diastolic function and impaired mitral valve function. There was altered expression of Ca2+ signaling molecules and the gap junction proteins, Connexin 43 and 45. Sarcoplasmic reticulum associated Ca2+-handling proteins (including the cardiac ryanodine receptor, sarco/endoplasmic reticulum Ca2+-ATPase, and cardiac calsequestrin) were down-regulated in the transgenic hearts with increased expression of calreticulin.Conclusions/SignificanceWe show that in adult heart, up-regulated expression of calreticulin induces cardiomyopathy in vivo leading to heart failure. This is due to an alternation in changes in a subset of Ca2+ handling genes, gap junction components and left ventricle remodeling.

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“…A recent study based on tandem mass spectrometry showed that CaMKII and CK1 phosphorylates Cx45 in vitro (Bao et al, 2011). Specifically, CaMKII was found to phosphorylate serine 326, 381, 382, 384, 385, 387, and 393 along with threonine 337, whereas CK1 phosphorylate serine 326, 382, 384, 387, and 393.…”

Section: Phosphorylation – a Key Player In The Regulation Of Gap Juncmentioning

confidence: 99%

Managing the complexity of communication: regulation of gap junctions by post-translational modification

et al. 2013

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Gap junctions are comprised of connexins that form cell-to-cell channels which couple neighboring cells to accommodate the exchange of information. The need for communication does, however, change over time and therefore must be tightly controlled. Although the regulation of connexin protein expression by transcription and translation is of great importance, the trafficking, channel activity and degradation are also under tight control. The function of connexins can be regulated by several post translational modifications, which affect numerous parameters; including number of channels, open probability, single channel conductance or selectivity. The most extensively investigated post translational modifications are phosphorylations, which have been documented in all mammalian connexins. Besides phosphorylations, some connexins are known to be ubiquitinated, SUMOylated, nitrosylated, hydroxylated, acetylated, methylated, and γ-carboxyglutamated. The aim of the present review is to summarize our current knowledge of post translational regulation of the connexin family of proteins.

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Residual Cx45 and its relationship to Cx43 in murine ventricular myocardium

Cited by 26 publications

References 65 publications

Role of connexin-43 in protective PI3K-Akt-GSK-3β signaling in cardiomyocytes

Role of connexin-43 in protective PI3K-Akt-GSK-3β signaling in cardiomyocytes

Calreticulin Induces Dilated Cardiomyopathy

Managing the complexity of communication: regulation of gap junctions by post-translational modification

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