The proteins that form vertebrate gap junctions, the connexins, are highly regulated and have short (< 2 h) half-lives. Phosphorylation of connexin43 (Cx43) is generally known to affect gap junction assembly, channel gating and turnover. After finding dramatic effects on gap junctions with Akt inhibitors, we created an antibody specific for Cx43 phosphorylated on S373, a potential Akt substrate. We found S373 phosphorylation in cells and skin or heart almost exclusively in larger gap junctional structures that increased dramatically after wounding or hypoxia. We were able to mechanistically show that Akt-dependent S373 phosphorylation increases gap junction size and communication by completely eliminating interaction between Cx43 and ZO-1. Thus, phosphorylation on S373 acts as a molecular "switch" to rapidly increase gap junctional communication potentially leading to initiation of activation and migration of keratinocytes or ischemic injury response in skin and heart, respectively.
"The aCT1 peptide binds in the PDZ domain of ZO-1 and inhibits Cx43-ZO-1 interactions . The recent reports by Dunn et al. , again emphasise the importance of Cx43 interactions with ZO-1, via adhesive properties and interaction with the cytoskeleton, in epidermal integrity and repair . "
[Show abstract][Hide abstract] ABSTRACT: Gap junction proteins (connexins) are differentially expressed throughout the multiple layers of the epidermis. A variety of skin conditions arise with aberrant connexin expression or function and suggest that maintaining the epidermal gap junction network has many important roles in preserving epidermal integrity and maintaining homeostasis. Mutations in a number of connexins lead to epidermal dysplasias giving rise to a range of dermatological disorders of differing severity. 'Gain of function' mutations reveal connexin-mediated roles in calcium signalling within the epidermis. Connexins are intrinsically involved in epidermal innate immunity and inflammation control, and in wound repair. The therapeutic potential of targeting connexins to improve wound healing responses is now clear. This review discusses the role of connexins in epidermal integrity, and examines the emerging evidence that connexins act as epidermal sensors to a variety of mechanical, temperature, pathogen-induced and chemical stimuli. Connexins thus act as an integral component of the skin's protective barrier.
[Show abstract][Hide abstract] ABSTRACT: The malignancy of glioblastoma multiform (GBM), the most common and aggressive form of human brain tumors, strongly correlates with the presence of hypoxic areas, but the mechanisms controlling the hypoxia-induced aggressiveness are still unclear. GBM cells express a number of ion channels whose activity supports cell volume changes and increases in the cytosolic Ca(2+) concentration, ultimately leading to cell proliferation, migration or death. In several cell types it has previously been shown that low oxygen levels regulate the expression and activity of these channels, and more recent data indicate that this also occurs in GBM cells. Based on these findings, it may be hypothesized that the modulation of ion channel activity or expression by the hypoxic environment may participate in the acquisition of the aggressive phenotype observed in GBM cells residing in a hypoxic environment. If this hypothesis will be confirmed, the use of available ion channels modulators may be considered for implementing novel therapeutic strategies against these tumors.
[Show abstract][Hide abstract] ABSTRACT: Gap junctions, composed of proteins from the connexin gene family, are highly dynamic structures that are regulated by kinase-mediated signaling pathways and interactions with other proteins. Phosphorylation of Connexin43 (Cx43) at different sites controls gap junction assembly, gap junction size and gap junction turnover. Here we present a model describing how Akt, mitogen activated protein kinase (MAPK) and src kinase coordinate to regulate rapid turnover of gap junctions. Specifically, Akt phosphorylates Cx43 at S373 eliminating interaction with zona occludens-1 (ZO-1) allowing gap junctions to enlarge. Then MAPK and src phosphorylate Cx43 to initiate turnover. We integrate published data with new data to test and refine this model. Finally, we propose that differential coordination of kinase activation and Cx43 phosphorylation controls the specific routes of disassembly, e.g., annular junction formation or gap junctions can potentially "unzip" and be internalized/endocytosed into the cell that produced each connexin.
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