Connexin 43: Key roles in the skin

Abstract

Gap junctions are tightly packed intercellular channels that serve a common purpose of allowing the intercellular exchange of small metabolites, second messengers and electrical signals. Connexins (Cxs) are gap junction proteins. Currently, 20 and 21 members of Cxs have been characterized in mice and humans, respectively. Connexin 43 (Cx43) is the most ubiquitously expressed type of Cx in the skin. It is produced by various different types of skin cell, such as keratinocytes, fibroblasts, endothelial and basal cells, melanocytes and dermal papilla cells. At present, more evidence indicates that Cx43 has an important role in skin repair and skin tumor development, as well as in skin cell invasion and metastasis. In this review, current knowledge regarding the regulation and function of Cx43 is summarized and the therapeutic potential of regulating Cx43 activity is discussed.

Keywords: connexin 43; gap junction; mimetic peptides; skin diseases; wound healing.

Figure 1.

Schematic of the regulation and function of Cx43 in acute skin injury. Elevated cAMP and pAKT at wound edges alter the expression and phosphorylation levels of Cx43. By mediating the upregulation of Col I, Col III, MMP2, TGF-β1 and VEGF, and the downregulation of Ccl2 and TNFα, Cx43 participates in the important wound healing processes, including ECM remodeling, epidermal/dermal cell proliferation and migration, inflammation response and angiogenesis. In addition, dysphosphorylation of Cx43 affects its interaction with other proteins, such as CASK and ZO-1, and subsequently modulates cell permeability and migration. Overall, Cx43 integrates multiple pathogenic signals to regulate wound healing. Cx43, connexin 43; cAMP, cyclic adenosine monophosphate; pAKT, phosphorylated AKT; Col, collagen; MMP2, matrix metalloproteinase-2; TGF-1, transforming growth factor; VEGF, vascular endothelial growth factor; Ccl2, chemokine (C-C motif) ligand 2; TNFα, tumor necrosis factor; ECM, extracellular matrix; CASK, calcium/calmodulin-dependent serine protein kinase; ZO-1, zonula occludens-1.