Phosphorylation of Connexin43 and Regulation of Cardiac Gap Junction

Imanaga, Issei; Hirosawa, Nobue; Lin, Hai; Sakamoto, Youichi; Matsumura, Takashi; K, Mayama

doi:10.1007/978-1-4615-1155-7_7

Cited by 10 publications

(11 citation statements)

References 35 publications

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“…Accordingly, antiarrhythmic effects of omega-3 in young SHRs were associated particularly with elimination of deficient Cx43 phosphorylation but in old SHRs also with increased total Cx43 expression and normalization of elevated Cx43 mRNA. Because Cx43 is a phosphoprotein, the changes in its phosphorylation state modulate channel function, that is, the degree of cell-to-cell electrical coupling [36][37][38] as well as its membrane distribution [17,39]. It is also known that protection from ventricular fibrillation can be in part attributed to enhanced myocardial Cx43 phosphorylation due to omega-3 intake or even due to disease itself, for example, diabetes [18].…”

Section: Discussionmentioning

confidence: 99%

Dietary omega-3 fatty acids attenuate myocardial arrhythmogenic factors and propensity of the heart to lethal arrhythmias in a rodent model of human essential hypertension

Radošinská

Bačová

Knézl

et al. 2013

Journal of Hypertension

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Section: Discussionmentioning

confidence: 99%

Dietary omega-3 fatty acids attenuate myocardial arrhythmogenic factors and propensity of the heart to lethal arrhythmias in a rodent model of human essential hypertension

Radošinská

Bačová

Knézl

et al. 2013

Journal of Hypertension

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“…Cx43 phosphorylation within the same cell type shows conflicting effects depending on the residues involved. For example, in human cardiac cells, Cx43 serine phosphorylation at residues S364, S365, and S369 increased GJIC, while that at residues S262, S368, and S372, reduced GJIC (Imanaga et al, 2004). In contrast, phosphorylation of Cx43 at S368 in folliculostellate cells increased GJIC (Meilleur et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid regulates gap junction intercellular communication in human endometrial stromal cells through modulation of the phosphorylation status of connexin 43

Taylor

Sidell

2012

Journal Cellular Physiology

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Previous studies revealed that gap junction intercellular communication (GJIC) among uterine stromal cells plays critical roles in modulating decidualization, neovasularization, and embryo implantation. Connexin (Cx) proteins are the major component of gap junctions and Cx43 is the most widely expressed connexin in endometrium. Phosphorylation of Cx43 was found to impair gap junction communication in this tissue. Using primary human endometrial stromal cells (ESCs) and a stable high telomerase-expressing ESC transfectant (T-HESC), we found that retinoic acid (RA) altered the phosphorylation status of Cx43 protein such that there was a decrease in the phosphorylated (P1 and P2) species accompanied by an increase in the non-phosphorylated (P0) form. This process is dependent on protein phosphatase 2A (PP2A) activity since selective PP2A inhibitors prevented the ability of RA to dephosphorylate Cx43. Although RA had no effect on total PP2A expression or activity, it significantly increased the intracellular association of Cx43 and PP2A. Inhibition of transcription and protein synthesis by actinomycin D and cycloheximide, respectively, had no effect on the RA-induced changes in the Cx43 phosphorylation pattern. Furthermore, BMS493, a potent antagonist of the classical RA-mediated transcriptional pathway, did not inhibit RA-induced Cx43 dephosphorylation. Our data indicate that RA stimulates physical association of PP2A with Cx43, resulting in the dephosphorylation of Cx43 and, as a consequence, up-regulation of GJIC in ESCs. This process is independent of new mRNA and protein synthesis and suggests a novel mechanism by which aberrant retinoid metabolism can explain certain reproductive disorders manifested by dysfunctional endometrial cell GJIC.

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“…Inc., USA) was used at dilutions of 1:5,000. The Western blotting procedures have been previously described [27].…”

Section: Immunoblot and Immunohistochemstry Of Cx43mentioning

confidence: 99%

“…To evaluate the functional cell-to-cell coupling, the conduction velocity and the longitudinal internal resistance were measured in the isolated muscle preparation as previously described [27].…”

Section: Evaluation Of Electrical Cell-to-cell Couplingmentioning

confidence: 99%

Alterations of Connexin 43 in the Diabetic Rat Heart

Lin¹,

Ogawa²,

Imanaga

et al. 2006

Cardiovascular Gap Junctions

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In the streptozotocin-induced diabetic rat heart, a decrease in the conductivity and suppression of electrical cell-to-cell coupling has been observed. To clarify this mechanism, the present study was performed to investigate the gap junction connexin 43 (Cx43) using immunohistochemistry, immunoblot, electron-microscopic analyses. Enhanced activation of PKCepsilon, augmentation of PKCepsilon-mediated phosphorylation of Cx43, a decrease in the total amount of Cx43, a reduction in the number of immunoreactive particles for Cx43 at the intercalated disk and internalization, annular profiles of the gap junction were all recognized in the diabetic heart. Such a deterioration in the expression of Cx43 was alleviated by treatment with either lysosomal (leupeptin) or proteasomal inhibitor (ALLN). These results suggest that the PKCepsilon-mediated hyperphosphorylation of Cx43 makes Cx43 vulnerable to proteolytic degradation, while a decrease in the conductivity in the diabetic heart is also caused by a decrease in the number of gap junction channels due to an acceleration of the proteolytic degradation of Cx43. The remodeling of Cx43 induced by the activation of PKC may therefore contribute to the formation of the arrhythmogenic substrate.

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Phosphorylation of Connexin43 and Regulation of Cardiac Gap Junction

Cited by 10 publications

References 35 publications

Dietary omega-3 fatty acids attenuate myocardial arrhythmogenic factors and propensity of the heart to lethal arrhythmias in a rodent model of human essential hypertension

Dietary omega-3 fatty acids attenuate myocardial arrhythmogenic factors and propensity of the heart to lethal arrhythmias in a rodent model of human essential hypertension

Retinoic acid regulates gap junction intercellular communication in human endometrial stromal cells through modulation of the phosphorylation status of connexin 43

Alterations of Connexin 43 in the Diabetic Rat Heart

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