Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

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.

Connexin Hemichannel Mimetic Peptide Attenuates Cortical Interneuron Loss and Perineuronal Net Disruption Following Cerebral Ischemia in Near-Term Fetal Sheep

“…Further, experimental inhibition of ECM protease activity was reported to reduce neural injury following stroke in adult rodents [126,129]. Finally, in other tissues such as spinal cord injury, skin, and cornea of the eye wounds, connexin43 hemichannel opening is associated with development of extracellular matrix fibrosis [130][131][132]. Thus, speculatively, pathological connexin43 hemichannel-mediated astrocytosis after perinatal HI may result in aberrant ECM remodeling in the brain, including altered development and/or degradation of cortical PNNs.…”

Connexins and the Epithelial Tissue Barrier: A Focus on Connexin 26

“…Many diseases have been linked with mutations in connexins, commonly termed connexin channelopathies [ 57 , 58 , 59 , 60 ]. CX43 is the most abundant connexin in the human skin; however, mutations and dysregulation of CX26, which is expressed at very low levels in healthy human epidermis, are related with skin disease characterised by abnormal keratinisation and hyperproliferation of the stratum corneum.…”

Comparative Analysis of Cx31 and Cx43 in Differentiation-Competent Rodent Keratinocytes

“…These patients suffer from transient erythematous patches and hyperkeratotic plaques [ 49 , 50 , 51 ]. Subsequent studies have assigned hyperactive Cx43 hemichannels as the potential cause of this skin pathology [ 24 , 25 ]. It should be noted that Cx43 gene mutations may evoke a distinctly different phenotypic status compared to complete Cx43 ablation as the mechanisms by which a Cx43 mutant can evoke a disease may include gain-of-function pathological interactions with other connexin family members [ 48 ].…”

“…Collectively, these in vivo and in vitro findings point to the likelihood that Cx43 and Cx31 serve very different roles in the epidermis and point to a potential essential role for Cx43. The importance of these connexins in the skin is further emphasized by the fact that mutations in the genes encoding both Cx31 and Cx43 can lead to erythrokeratodermia variabilis et progressiva [ 1 , 24 , 25 ].…”