PDF(Pubmed)
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.
摘要：
表皮，皮肤的最外层，作为对外部因素的保护屏障。表皮分化,对表皮稳态至关重要的严格调控过程，表皮屏障的形成和皮肤完整性的维护，由几个玩家精心策划，包括信号分子，钙梯度和连接复合物，如间隙连接（GJs）。GJ蛋白,连接蛋白可促进相邻角质形成细胞之间的细胞间通讯。连接蛋白可以作为半通道或GJ，取决于它们与邻近角质形成细胞的其他连接子的相互作用。这些通道能够运输代谢物，cAMP,microRNAs,和离子，包括Ca2+，穿过细胞膜。至少10种不同的连接蛋白在表皮内表达,并且其中至少5种的突变与各种皮肤病有关。连接蛋白突变可能通过改变其合成而导致异常的通道活性，它们的门控属性，它们的胞内贩运，以及半通道和GJ通道的集合。除了突变,连接蛋白表达在其他皮肤病包括牛皮癣中失调，慢性伤口和皮肤癌，表明连接蛋白在皮肤稳态中的关键作用。对于具有突变或改变的连接蛋白的病症的当前治疗选择是有限的,并且主要集中于症状管理。几种疗法，包括非肽化学物质，抗体，模拟肽和等位基因特异性小干扰RNA在治疗与连接蛋白相关的皮肤疾病中很有希望.由于连接蛋白在维持表皮稳态中起着至关重要的作用，如与一系列皮肤病和癌症有关，需要进一步的研究来破译由于突变或表达改变而引起的细胞内的分子和细胞变化，导致异常增殖和分化。这也将有助于表征每个同工型在皮肤稳态中的作用，除了开发创新的治疗干预措施。这篇综述强调了表皮中连接蛋白的关键功能以及连接蛋白与皮肤疾病之间的关联。并讨论了潜在的治疗选择。
