Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

Abstract

Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin‐like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin‐based and pannexin‐based channels in noncancerous liver disease.

A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

“…Finally, for a number of variant gene-pairs, the observed effect on NAFLD risk and the impact of gene expression in the liver was consistent with our understanding of the expected effect given what is known about gene function, suggesting possible relevance as therapeutic targets. Among those, genetic deletion of Pannexin 1 (encoded by PANX1 ) was reported to have a protective effect in mouse model of acute and chronic liver disease 43,44 , and is consistent with the data we report here.…”

Pirfenidone attenuates homocysteine‑induced apoptosis by regulating the connexin 43 pathway in H9C2 cells

“…connexin is the basic building block of the gap junction channel (17). cx43 is widely involved in the development of diseases, such as the regulation of cell growth, proliferation, apoptosis and homeostasis (17,29). connexin mimetic peptides, such as gap26, are known to be inhibitors of gap junction channels (30).…”

Mechanisms Underlying Connexin Hemichannel Activation in Disease

“…Among those are gap junctions, which form cell-to-cell junctions that facilitate direct intercellular communication between cells by allowing the passage of small and hydrophilic molecules, including glucose, glutamate, glutathione, adenosine triphosphate (ATP), cyclic adenosine monophosphate, inositol triphosphate and ions, such as calcium, sodium and potassium [1]. These communicating cell-to-cell junctions serve as gatekeepers for many physiological processes [2,3]. They arise from the interaction of two hemichannels, which in turn are built up by six connexin proteins at the cell plasma membrane surface of adjacent cells.…”

“…The different connexin family members are designated based upon their molecular weight as predicted by cDNA sequencing. In this respect, connexin43 (Cx43), which is the most abundantly expressed connexin variant, has a molecular mass of 43 kDa [1][2][3].…”

“…While gap junctions mediate intercellular communication, connexin hemichannels support the transport of messengers between the cytosol and the extracellular environment. Unlike gap junctions, connexin hemichannels become predominantly active under pathological conditions (Table 1) [2,3,5]. The current mini-review provides an overview of the machinery involved in connexin hemichannel opening in disease.…”