Gap junction alpha-1 protein (Connexin 43) C-terminal domain (Cx43-CT)

The Connexin 43 (Cx43) C-terminal domain is a 150-amino acid cytoplasmic tail of the Gap junction alpha-1 protein that functions as a critical regulatory scaffold for gap junction and hemichannel activity (UniProt P17302). This domain is characterized by its intrinsically disordered structure and contains multiple phosphorylation sites and protein-protein interaction motifs, most notably a C-terminal PDZ-binding motif that interacts with Zonula occludens-1 (ZO-1) (Gourdie et al., 2019). These interactions are vital for controlling the trafficking of Cx43 and its assembly into gap junction plaques, which facilitate direct intercellular communication. In various diseases, including chronic wounds and cardiac arrhythmias, the dysregulation of the Cx43 C-terminal domain leads to impaired gap junctional coupling and the pathological opening of hemichannels, which release pro-inflammatory signals (Ghatnekar et al., 2009). Therapeutic agents like the mimetic peptide alpha-CT1 (Granexin) target this domain by competing for the ZO-1 binding site, thereby promoting gap junction stability and reducing hemichannel-mediated inflammation (Jiang et al., 2015). By modulating these C-terminal interactions, drugs aim to restore homeostatic cellular coupling and limit tissue damage in conditions such as diabetic foot ulcers and myocardial infarction. The domain also serves as a substrate for various kinases, including PKC and MAPK, which modulate the channel's open probability and half-life (Solan & Lampe, 2014). Consequently, the Cx43 C-terminal domain represents a significant pharmacological target for modulating tissue repair and electrical stability in the heart.

Other names

GJA1 C-terminal domainConnexin-43 C-terminusCx43-CTDGap junction alpha-1 protein C-terminal tail

Competitive inhibition of the interaction between the Cx43 C-terminal PDZ-binding motif and the PDZ2 domain of Zonula occludens-1 (ZO-1), which promotes the sequestration of Cx43 hemichannels into gap junction plaques and reduces pathological hemichannel activity (Gourdie et al., 2019).