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Connexin-43 in Cancer: Above and Beyond Gap Junctions!
Cancers (Basel)
December 2024
School of Medicine, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Connexin-43 (Cx43) is the most characterized gap junction protein, primarily involved in the Gap Junctional Intercellular Communication (GJIC) between adjacent cells to facilitate molecule exchange and the formation of a signaling network. It is increasingly evident that the importance of Cx43 is not only limited to its GJIC function, but rather includes its role in connecting the intracellular and extracellular environment by forming membrane hemichannels, as well as its intracellular signaling function mediated by its C-terminal tail (Cx43-CT). Notably, Cx43 has been implicated in a variety of cancers, with earlier notions suggesting a tumor-suppressor function, whereas new studies shed light on its pro-tumorigenic role.
View Article and Find Full Text PDFConnexin 43 and Pannexin 1 hemichannels as endogenous regulators of innate immunity in sepsis.
Front Immunol
January 2025
The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.
Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infections that is initiated by the body's innate immune system. Nearly a decade ago, we discovered that bacterial lipopolysaccharide (LPS) and serum amyloid A (SAA) upregulated Connexin 43 (Cx43) and Pannexin 1 (Panx1) hemichannels in macrophages. When overexpressed, these hemichannels contribute to sepsis pathogenesis by promoting ATP efflux, which intensifies the double-stranded RNA-activated protein kinase R (PKR)-dependent inflammasome activation, pyroptosis, and the release of pathogenic damage-associated molecular pattern (DAMP) molecules, such as HMGB1.
View Article and Find Full Text PDFMechanism of connexin channel inhibition by mefloquine and 2-aminoethoxydiphenyl borate.
PLoS One
December 2024
Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
Gap junction intercellular communication (GJIC) between two adjacent cells involves direct exchange of cytosolic ions and small molecules via connexin gap junction channels (GJCs). Connexin GJCs have emerged as drug targets, with small molecule connexin inhibitors considered a viable therapeutic strategy in several diseases. The molecular mechanisms of GJC inhibition by known small molecule connexin inhibitors remain unknown, preventing the development of more potent and connexin-specific therapeutics.
View Article and Find Full Text PDFBlockade of connexin43-containing hemichannel attenuates the LPS-induced inflammatory response in human dental pulp cells by inhibiting the extracellular flux of ATP and HMGB1.
Front Oral Health
December 2024
School of Stomatology, Southwest Medical University, Lu Zhou, China.
Introduction: Tissue repair can be promoted by moderate inflammation but suppressed by excessive levels. Therefore, control of excessive inflammation following removal of infection plays a critical role in promotion of pulpal repair. Connexin 43 (Cx43) forms hemichannels (HCs) or gap channels (GJs) to facilitate the delivery of small molecules between cells to regulate both inflammation and repair.
View Article and Find Full Text PDFConnexin 43 hemichannels and related diseases.
Antib Ther
October 2024
Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229, United States.
Connexin 43 (Cx43) protein forms hemichannels (connexons) and gap junctions, with hemichannels consisting of six Cx43 molecules and gap junctions formed by two hemichannels. While gap junctions are prevalent in organs like the heart and liver, hemichannels are found in specific cell types, such as astrocytes and osteocytes. They allow the passage of small molecules (<1.
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