Connexins play vital roles in hearing, including promoting cochlear development and sustaining auditory function in the mature cochlea. Mutations in connexins expressed in the cochlear epithelium, Cx26 and Cx30, cause sensorineural deafness and in the case of Cx26, is one of the most common causes of non-syndromic, hereditary deafness. Connexins function as gap junction channels and as hemichannels, which mediate intercellular and transmembrane signaling, respectively. Both channel configurations can play important, but very different roles in the cochlea. The potential roles connexin hemichannels can play are discussed both in normal cochlear function and in promoting pathogenesis that can lead to hearing loss.
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http://dx.doi.org/10.1016/j.neulet.2017.09.020 | DOI Listing |
Int J Mol Sci
January 2025
Programa de Comunicación Celular en Cáncer, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7550000, Chile.
DUX4 is typically a repressed transcription factor, but its aberrant activation in Facioscapulohumeral Muscular Dystrophy (FSHD) leads to cell death by disrupting muscle homeostasis. This disruption affects crucial processes such as myogenesis, sarcolemma integrity, gene regulation, oxidative stress, immune response, and many other biological pathways. Notably, these disrupted processes have been associated, in other pathological contexts, with the presence of connexin (Cx) hemichannels-transmembrane structures that mediate communication between the intracellular and extracellular environments.
View Article and Find Full Text PDFCancers (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 PDFFront 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 PDFPLoS 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 PDFJ Cell Biol
March 2025
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA.
While membrane proteins such as ion channels continuously turn over and require replacement, the mechanisms of specificity of efficient channel delivery to appropriate membrane subdomains remain poorly understood. GJA1-20k is a truncated Connexin43 (Cx43) isoform arising from translation initiating at an internal start codon within the same parent GJA1 mRNA and is requisite for full-length Cx43 trafficking to cell borders. GJA1-20k does not have a full transmembrane domain, and it is not known how GJA1-20k enables forward delivery of Cx43 hemichannels.
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