Abstract
Gap junctional channels are specialized components of the cellular membrane that allow the intercellular passage of small metabolites, ions, and second messengers to maintain homeostasis. They are comprised of members of the connexin gene family that encode a wide array of proteins that are expressed in nearly every tissue type. Cx43 is perceived to be the most broadly expressed connexin in humans, with several genetic skin diseases being linked to Cx43 mutations specifically. These mutations, in large, produce a gain of functional hemichannels that contribute to the phenotypes of Erythrokeratoderma Variabilis et Progressiva (EKVP), Palmoplantar Keratodemra Congenital Alopecia-1 (PPKCA1), and others that produce large conductance and increased permselectivity in otherwise quiescent structures. Gaining functional hemichannels can have adverse effects in the skin, inducing apoptosis via Ca2+ overload or increased ATP permeability. Here, we review the link between Cx43 and skin disease. We aim to provide insight into the mechanisms regulating the normal and pathophysiological gating of these essential proteins, as well as address current therapeutic strategies. We also demonstrate that transient transfection of neuro-2a (N2a) cells with mutant Cx43 cDNA resulted in increased hemichannel activity compared to wild-type Cx43 and untransfected cells, which is consistent with other studies in the current literature.
Highlights
Intercellular communication is critical for cellular and tissue homeostasis within multicellular organisms, allowing for the transport of signaling molecules
In order to form a complete gap junctional channel, six connexin subunits must oligomerize into a hemichannel, and must attach to an adjacent hemichannel located on the plasma membrane of another cell
We demonstrated that three Cx43 mutations linked to diseases of the epidermis, Cx43-G8V, Cx43-E227D, and Cx43-A44V, formed functioning hemichannels that mediated increased membrane current flow, suggesting a potential common feature of genetic skin disease related to this protein [69]
Summary
Intercellular communication is critical for cellular and tissue homeostasis within multicellular organisms, allowing for the transport of signaling molecules. In a mouse model of ODDD, there was an observed reduction in Cx43 expression overall, with marked decreases in gap junction coupling and plaque number, indicating certain mutations in GJA1 may be more dominant [30]. Two heterozygous Cx43 mutants found in the bladder were studied in another ODDD mouse model, where it was found that both mutations resulted in decreased Cx43 gap junctional intercellular communication and act in a dominant manner to display defects in bladder function [31]. There are several human skin diseases that are associated with mutations in Cx43 These diseases, namely Oculodentodigital Dysplasia (ODDD) and Palmoplantar Keratoderma and Congenital Alopecia-1 (PPKCA1), among others, result in a gain in the number of functioning hemichannels across the cell membrane. Given its ubiquitous nature, understanding its mechanism of action in each tissue, determining the level of co-expression with other connexins, and implementing therapeutic strategies for patients with these inflammatory diseases provides an ongoing challenge to current research
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