Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions

Abstract

The epidermis, the outermost layer of the skin, serves as a protective barrier against external factors. Epidermal differentiation, a tightly regulated process essential for epidermal homeostasis, epidermal barrier formation and skin integrity maintenance, is orchestrated by several players, including signaling molecules, calcium gradient and junctional complexes such as gap junctions (GJs). GJ proteins, known as connexins facilitate cell-to-cell communication between adjacent keratinocytes. Connexins can function as either hemichannels or GJs, depending on their interaction with other connexons from neighboring keratinocytes. These channels enable the transport of metabolites, cAMP, microRNAs, and ions, including Ca²⁺, across cell membranes. At least ten distinct connexins are expressed within the epidermis and mutations in at least five of them has been linked to various skin disorders. Connexin mutations may cause aberrant channel activity by altering their synthesis, their gating properties, their intracellular trafficking, and the assembly of hemichannels and GJ channels. In addition to mutations, connexin expression is dysregulated in other skin conditions including psoriasis, chronic wound and skin cancers, indicating the crucial role of connexins in skin homeostasis. Current treatment options for conditions with mutant or altered connexins are limited and primarily focus on symptom management. Several therapeutics, including non-peptide chemicals, antibodies, mimetic peptides and allele-specific small interfering RNAs are promising in treating connexin-related skin disorders. Since connexins play crucial roles in maintaining epidermal homeostasis as shown with linkage to a range of skin disorders and cancer, further investigations are warranted to decipher the molecular and cellular alterations within cells due to mutations or altered expression, leading to abnormal proliferation and differentiation. This would also help characterize the roles of each isoform in skin homeostasis, in addition to the development of innovative therapeutic interventions. This review highlights the critical functions of connexins in the epidermis and the association between connexins and skin disorders, and discusses potential therapeutic options.

Keywords: connexins; dysregulation; epidermal homeostasis; mutations; skin disorders; therapeutic approaches.

FIGURE 1

Structure of connexins and gap junctions (GJs) (A) Connexins are composed of four transmembrane domains (TM1-TM4) with intracellular N- and C-terminal domains and two extracellular loops (EL1 and EL2). (B) Connexins can oligomerize to form hemichannels, which can be either homomeric (composed of a single type of connexin) or heteromeric (composed of different types of connexins). (C) Hemichannels on the plasma membrane can interlock with connexons of the same or different types on the cell membrane to form homotypic or heterotypic GJ channels, respectively. Created with BioRender (2023).

FIGURE 2

Connexins and GJ biosynthesis. Connexins are inserted into the endoplasmic reticulum-Golgi network (i) and can be degraded in proteasomes (ix). They assemble into connexons/hemichannels and transported to the plasma membrane (ii, iii), where they can form GJ channels with adjacent cells (iv) or function as individual hemichannels on the membrane (iii). GJs can be endocytosed to create connexosomes (v), which may be degraded by endosome-lysosome route (vi). Connexins are sorted from early endosomes to lysosomes (viii) or recycled to the plasma membrane (vii). Created with BioRender (2023).

FIGURE 3

Connexin distribution within different layers of the epidermis. Basal cells primarily express Cx43 while Cx26, Cx30, Cx30.3, Cx31, Cx31.1, Cx40, Cx43 and Cx45 are observed in cells of spinosum layer. Keratinocytes of granulosum have differential expression of Cx26, Cx30.3, Cx31, Cx31.1, Cx40, Cx43, and Cx45. Created with BioRender (2023).

FIGURE 4

The effects of skin-associated connexin mutations on connexins and/or channels. Depending on the mutation type and location on the proteins, they can cause trafficking defects leading to retention of proteins in the cytosol. They inhibit the channel activity on the plasma membrane (loss-of-function). Additionally, mutations can have an inhibitory effects on other connexins expressed within the same cell. Finally, they can induce the dormation of hyperactive hemichannels, resulting in uncontrolled molecular exchange across the plasma membrane. Created with BioRender (2023).