Mechanisms Underlying Connexin Hemichannel Activation in Disease

Campenhout, Raf Van; Gomes, Ana Rita Coelho; Groof, Timo W.M. De; Devoogdt, Nick; Vinken, Mathieu

doi:10.3390/ijms22073503

Cited by 31 publications

(28 citation statements)

References 94 publications

(164 reference statements)

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“…Hemichannels regulate extracellular communications, especially allowing the dissemination of disease. Cx43 is also involved in various signalling transduction pathways that interact individually with intracellular proteins [ 1 , 2 , 3 , 18 , 19 ]. Cx43 can undergo some posttranslational modifications, including phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that a decreased Cx43 phosphorylation at serine 368 increases arrhythmia occurrence in cultured cardiac myocytes and in vivo in animal models. However, the outcome of Cx43 phosphorylation depends on the type of the kinase, the cell target, and the cellular context [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, the sections were treated with 0.2% triton-X100/PBS for antigen retrieval and successively with blocking solution (BS, 0.1% Tween, 0.25% BSA in PBS) for 1 h at room temperature (RT). Then, the samples were incubated overnight at 4 °C with previously tested primary antibodies [ 7 , 19 , 27 ] diluted in BS (see Table 3 ).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Madonna

Moscato

Polizzi

et al. 2021

IJMS

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Cardiac connexins (Cxs) are proteins responsible for proper heart function. They form gap junctions that mediate electrical and chemical signalling throughout the cardiac system, and thus enable a synchronized contraction. Connexins can also individually participate in many signal transduction pathways, interacting with intracellular proteins at various cellular compartments. Altered connexin expression and localization have been described in diseased myocardium and the aim of this study is to assess the involvement of Cx43, Cx26, and some related molecules in ponatinib-induced cardiac toxicity. Ponatinib is a new multi-tyrosine kinase inhibitor that has been successfully used against human malignancies, but its cardiotoxicity remains worrisome. Therefore, understanding its signaling mechanism is important to adopt potential anti cardiac damage strategies. Our experiments were performed on hearts from male and female mice treated with ponatinib and with ponatinib plus siRNA-Notch1 by using immunofluorescence, Western blotting, and proteomic analyses. The altered cardiac function and the change in Cxs expression observed in mice after ponatinib treatment, were results dependent on the Notch1 pathway and sex. Females showed a lower susceptibility to ponatinib than males. The downmodulation of cardiac Cx43, Cx26 and miR-122, high pS368-Cx43 phosphorylation, cell viability and survival activation could represent some of the female adaptative/compensatory reactions to ponatinib cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Madonna

Moscato

Polizzi

et al. 2021

IJMS

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“…With evidence that Cx43 hemichannel mediated communication contributes to the pathogenesis and progression of tissue damage in secondary complications of diabetes [ 49 , 107 , 108 ], drugs that target Cx43 hemichannels have been identified as potential anti-inflammatory therapies [ 109 , 110 ]. Compounds of interest include Peptide 5, known to bind to the second extracellular loop of Cx43 [ 111 ]; Gap26, which mimics the first extracellular loop of Cx43 [ 112 ]; and αCT1, a Cx43-based peptide [ 113 ].…”

Section: Cx43 Hemichannel Blockers and Treatment Of Inflammation In Diabetes And Its Secondary Complicationsmentioning

confidence: 99%

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

Cliff

Williams

Chadjichristos

et al. 2022

IJMS

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Of increasing prevalence, diabetes is characterised by elevated blood glucose and chronic inflammation that precedes the onset of multiple secondary complications, including those of the kidney and the eye. As the leading cause of end stage renal disease and blindness in the working population, more than ever is there a demand to develop clinical interventions which can both delay and prevent disease progression. Connexins are membrane bound proteins that can form pores (hemichannels) in the cell membrane. Gated by cellular stress and injury, they open under pathophysiological conditions and in doing so release ‘danger signals’ including adenosine triphosphate into the extracellular environment. Linked to sterile inflammation via activation of the nod-like receptor protein 3 inflammasome, targeting aberrant hemichannel activity and the release of these danger signals has met with favourable outcomes in multiple models of disease, including secondary complications of diabetes. In this review, we provide a comprehensive update on those studies which document a role for aberrant connexin hemichannel activity in the pathogenesis of both diabetic eye and kidney disease, ahead of evaluating the efficacy of blocking connexin-43 specific hemichannels in these target tissues on tissue health and function.

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“…The effects of connexins, the activity of which is under the direct control of external Ca 2+ [ 17 , 18 ], have not been practically investigated for WAT. Global calcium dynamics regulates key intracellular processes in healthy adipose tissue—differentiation, lipid accumulation and insulin signaling [ 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of Cx43 Hemichannels Induces the Generation of Ca2+ Oscillations in White Adipocytes and Stimulates Lipolysis

Turovsky

Varlamova

Turovskaya

2021

IJMS

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The aim of the study was to investigate the mechanisms of Ca2+ oscillation generation upon activation of connexin-43 and regulation of the lipolysis/lipogenesis balance in white adipocytes through vesicular ATP release. With fluorescence microscopy it was revealed that a decrease in the concentration of extracellular calcium ([Ca2+]ex) results in two types of Ca2+ responses in white adipocytes: Ca2+ oscillations and transient Ca2+ signals. It was found that activation of the connexin half-channels is involved in the generation of Ca2+ oscillations, since the blockers of the connexin hemichannels—carbenoxolone, octanol, proadifen and Gap26—as well as Cx43 gene knockdown led to complete suppression of these signals. The activation of Cx43 in response to the reduction of [Ca2+]ex was confirmed by TIRF microscopy. It was shown that in response to the activation of Cx43, ATP-containing vesicles were released from the adipocytes. This process was suppressed by knockdown of the Cx43 gene and by bafilomycin A1, an inhibitor of vacuolar ATPase. At the level of intracellular signaling, the generation of Ca2+ oscillations in white adipocytes in response to a decrease in [Ca2+]ex occurred due to the mobilization of the Ca2+ ions from the thapsigargin-sensitive Ca2+ pool of IP3R as a result of activation of the purinergic P2Y1 receptors and phosphoinositide signaling pathway. After activation of Cx43 and generation of the Ca2+ oscillations, changes in the expression levels of key genes and their encoding proteins involved in the regulation of lipolysis were observed in white adipocytes. This effect was accompanied by a decrease in the number of adipocytes containing lipid droplets, while inhibition or knockdown of Cx43 led to inhibition of lipolysis and accumulation of lipid droplets. In this study, we investigated the mechanism of Ca2+ oscillation generation in white adipocytes in response to a decrease in the concentration of Ca2+ ions in the external environment and established an interplay between periodic Ca2+ modes and the regulation of the lipolysis/lipogenesis balance.

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Mechanisms Underlying Connexin Hemichannel Activation in Disease

Cited by 31 publications

References 94 publications

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

Activation of Cx43 Hemichannels Induces the Generation of Ca2+ Oscillations in White Adipocytes and Stimulates Lipolysis

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