Connexin 43-serine 282 modulates serine 279 phosphorylation in cardiomyocytes
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Connexins are crucial cardiac proteins that form hemichannels and gap junctions. Gap junctions are responsible for the propagation of electrical and chemical signals between myocardial cells and cells of the specialized conduction system in order to synchronize the cardiac cycle and steer cardiac pump function. Gap junctions are normally open, while hemichannels are closed, but pathological circumstances may close gap junctions and open hemichannels, thereby perturbing cardiac function and homeostasis. Current evidence demonstrates an emerging role of hemichannels in myocardial ischemia and arrhythmia, and tools are now available to selectively inhibit hemichannels without inhibiting gap junctions as well as to stimulate hemichannel incorporation into gap junctions. We review available experimental evidence for hemichannel contributions to cellular pro-arrhythmic events in ventricular and atrial cardiomyocytes, and link these to insights at the level of molecular control of connexin-43-based hemichannel opening. We conclude that a double-edged approach of both preventing hemichannel opening and preserving gap junctional function will be key for further research and development of new connexin-based experimental approaches for treating heart disease.
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Mutations in the genes for three different isotypes of the gap junction channel protein connexin are associated with deafness. This indicates an important role for gap junctions in auditory function and provides an opportunity to explore structure-function relationships in the connexin molecule. We have been examining the distribution of gap junctions and the pattern of connexin expression in the mature inner ear and during development, and the effect of specific mutations on the processing and functionality of the expressed connexin proteins in an in vitro system.
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This review comes after the International Gap Junction Conference (IGJC 2015) and describes the current knowledge on the function of the specific motifs of connexins in the regulation of the formation of gap junction channels. Moreover the review is complemented by a summarized description of the distinct contribution of gap junction channels in the electrical coupling. Complementary biochemical and functional characterization on cell models and primary cells have improved our understanding on the oligomerization of connexins and the formation and the electrical properties of gap junction channels. Studies mostly focused cardiac connexins Cx43 and Cx40 expressed in myocytes, while Cx45 and Cx30.2 have been less investigated, for which main findings are reviewed to highlight their critical contribution in the formation of gap junction channels for ensuring the orchestrated electrical impulse propagation and coordination of atrial and ventricular contraction and heart function, whereas connexin dysfunction and remodeling are pro-arrhythmic factors. Common and specific motifs of residues identified in different domain of each type of connexin determine the connexin homo- and hetero-oligomerization and the channels formation, which leads to specific electrical properties. These motifs and the resulting formation of gap junction channels are keys to ensure the tissue homeostasis and function in each connexin expression pattern in various tissues of multicellular organisms. Altogether, the findings to date have significantly improved our understanding on the function of the different connexin expression patterns in healthy and diseased tissues, and promise further investigations on the contribution in the different types of connexin.
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Connexin are the basic structure and function protein of gap junction. About 20 connexin have been found in the mammals' tissues and organs so far. Cx43 is the most abundant protein in the gap junction protein, mainly exist in astrocytes. Cx43 plays an very important role in the communication of gap junction mediated by GJ. At present, About the Cx43's research is mainly concentrated in tumor, cardiovascular, epilepsy, cerebral edema, etc. This review presents a research progress between Cx43 and brain edema.
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In cardiac muscle, the gap junction plays a pivotal role in electrical cell-to-cell coupling and impulse propagation between cells. The function of the gap junction depends on the regulation of connexin in the gap junction channel. A dysfunction of the gap junction is possibly caused by the downregulation of connexin or one of arrhythmogenic factors. The mechanisms of ventricular fibrillation, a lethal tachyarrhythmia, have been studied in relation to the remodelling of connexin.To determine what type of connexin 43 (Cx43) remodelling contributes to the generation of ventricular fibrillation and what factors induce the modelling of Cx43.Aconitine-induced ventricular fibrillation was induced in hearts isolated from adult rats. Alterations in the electrical activity, the phosphorylation of Cx43 and the expression of Cx43 were evaluated by both intracellular and extracellular recording of the action potentials, Western blotting and immunohistochemistry, respectively. Flutter activity after the application of aconitine shifted spontaneously to fibrillation, showing an electrical interaction between neighbouring cells in close proximity to one another. The facility of the shift from flutter to fibrillation was evaluated as a susceptibility of the heart to fibrillation in relation to gap junction function. The effects of phorbol 12-myristate 13-acetate, angiotensin II (AII) analogues, AII antagonists, the diabetic state, protein kinase A (PKA) activator, cyclic AMP analogues, d-sotalol (class III antiarrhythmic drug) and PKA inhibitors on the susceptibility of the heart to fibrillation were examined.Pathological hearts with heterogeneous expression of Cx43 at the gap junction, such as phorbol 12-myristate 13-acetate-and AII analogue-treated hearts, as well as diabetic hearts, showed a significantly higher susceptibility to fibrillation. On the other hand, hearts with augmentative expression of Cx43 at the gap junction, such as hearts pretreated with a PKA activator, a cyclic AMP analogue (8-bromo-cyclic AMP) or d-sotalol, showed a significantly lower susceptibility to fibrillation. At the beginning of fibrillation, an increase in the cardiac tissue AII level, an augmentation of the protein kinase C (PKC)-epsilon activity, the presence of PKC-mediated hyperphosphorylation, a suppression of the PKA-mediated phosphorylation of Cx43 and a reduction in the expression of Cx43 at the gap junction were observed. These alterations in Cx43 expression were also observed to increase as the fibrillation advanced.Augmentation of PKC-mediated phosphorylation and suppression of PKA-mediated phosphorylation induces the downward remodelling of Cx43. Such remodelling of Cx43 induces asynchronous electrical activities and makes the ventricular tissue susceptible to fibrillation. PKC is activated by AII. The fibrillation itself remodels Cx43, thereby causing a vicious cycle. As a result, PKC inhibitors, AII antagonists and PKA activators are considered to possibly have a protective effect against the initiation or advancement of ventricular fibrillation.
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