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Connexins and their channels are involved in the control of all aspects of the cellular life cycle, ranging from cell growth to cell death, by mediating extracellular, intercellular and intracellular communication. These multifaceted aspects of connexin-related cellular signaling obviously require strict regulation. While connexin channel activity is mainly directed by posttranslational modifications, connexin expression as such is managed by classical cis/trans mechanisms. Over the past few years, it has become clear that connexin production is equally dictated by epigenetic actions. This paper provides an overview of the role of major determinants of the epigenome, including DNA methylation, histone acetylation and microRNA species, in connexin expression.

Background and aims Being goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for drug-induced liver insults. In the present study, the involvement of connexin26, connexin32 and connexin43, the building blocks of liver gap junctions, was investigated in acetaminophen-induced hepatotoxicity. Methods C57BL/6 mice were overdosed with 300 mg/kg body weight acetaminophen followed by analysis of the expression and localization of connexins as well as monitoring of hepatic gap junction functionality. Furthermore, acetaminophen-induced liver injury was compared between mice genetically deficient in connexin43 and wild type littermates. Evaluation of the toxicological response was based on a set of clinically relevant parameters, including protein adduct formation, measurement of alanine aminotransferase activity, cytokines and glutathione. Results It was found that gap junction communication deteriorates upon acetaminophen intoxication in wild type mice, which is associated with a switch in mRNA and protein production from connexin32 and connexin26 to connexin43. The upregulation of connexin43 expression is due, at least in part, to de novo production by hepatocytes. Connexin43-deficient animals tended to show increased liver cell death, inflammation and oxidative stress in comparison with wild type counterparts. Conclusion These results suggest that hepatic connexin43-based signaling may protect against acetaminophen-induced liver toxicity.

Research conducted over the past two decades has provided convincing evidence that cell death, and more specifically apoptosis, can exceed single cell boundaries and can be strongly influenced by intercellular communication networks. We recently reported that gap junctions (i.e. channels directly connecting the cytoplasm of neighboring cells) composed of connexin43 or connexin26 provide a direct pathway to promote and expand cell death, and that inositol 1,4,5-trisphosphate (IP3) diffusion via these channels is crucial to provoke apoptosis in adjacent healthy cells. However, IP3 itself is not sufficient to induce cell death and additional factors appear to be necessary to create conditions in which IP3 will exert proapoptotic effects. Although IP3-evoked Ca2+ signaling is known to be required for normal cell survival, it is also actively involved in apoptosis induction and progression. As such, it is evident that an accurate fine-tuning of this signaling mechanism is crucial for normal cell physiology, while a malfunction can lead to cell death. Here, we review the role of IP3 as an intracellular and intercellular cell death messenger, focusing on the endoplasmic reticulum-mitochondrial synapse, followed by a discussion of plausible elements that can convert IP3 from a physiological molecule to a killer substance. Finally, we highlight several pathological conditions in which anomalous intercellular IP3/Ca2+ signaling might play a role. This article is part of a Special Issue entitled:12th European Symposium on Calcium.

It is nowadays well established that gap junctions are critical gatekeepers of cell proliferation, by controlling the intercellular exchange of essential growth regulators. In recent years, however, it has become clear that the picture is not as simple as originally anticipated, as structural precursors of gap junctions can affect cell cycling by performing actions not related to gap junctional intercellular communication. Indeed, connexin hemichannels also foresee a pathway for cell growth communication, albeit between the intracellular compartment and the extracellular environment, while connexin proteins as such can directly or indirectly influence the production of cell cycle regulators independently of their channel activities. Furthermore, a novel set of connexin-like proteins, the pannexins, have lately joined in as regulators of the cell proliferation process, which they can affect as either single units or as channel entities. In the current paper, these multifaceted aspects of connexin-related signalling in cell cycling are reviewed. ispartof: Biochimica et Biophysica Acta. Reviews on Cancer vol:1815 issue:1 pages:13-25 ispartof: location:Netherlands status: published