Connexins in the nucleus: A review of emerging roles in cell signaling and gene regulation.

Connexins (Cxs) have long been recognized for their canonical roles in forming gap junction channels (GJCs), which mediate direct intercellular communication, and hemichannels, which enable the exchange of ions, metabolites, and signaling molecules between the cytoplasm and the extracellular environment. Through these functions, Cxs contribute to tissue homeostasis, electrical and metabolic coupling, and autocrine/paracrine signaling. Increasing evidence also indicates that Cxs participate in non-canonical intracellular processes, including protein-protein interactions, extracellular vesicle-mediated communication, and organelle-associated signaling. In this context, several studies have reported nuclear or nuclear-associated localization of specific Cx isoforms, raising the possibility that Cxs may influence gene expression and nuclear signaling pathways. However, these observations require careful interpretation because distinguishing nucleoplasmic localization from nuclear envelope association or perinuclear accumulation remains technically challenging. In addition, much of the available evidence derives from immunofluorescence analyses, biochemical fractionation, or overexpression systems. In this review, we examine the evidence supporting nuclear or nuclear-associated localization of Cx26, Cx30, Cx30.2, Cx43, and Cx46; distinguish between full-length proteins and Cx-derived fragments; summarize potential mechanisms involved in nuclear targeting; and discuss the possible functional implications of these findings in physiological and pathological contexts. Overall, current evidence supports the concept that nuclear or nuclear-associated Cx localization represents an emerging and context-dependent aspect of Cx biology that requires further mechanistic and in vivo validation.