Cx43 can form functional channels at the nuclear envelope and modulate gene expression in cardiac cells

Abstract

Classically associated with gap junction-mediated intercellular communication, connexin43 (Cx43) is increasingly recognized to possess non-canonical biological functions, including gene expression regulation. However, the mechanisms governing the localization and role played by Cx43 in the nucleus, namely in transcription modulation, remain unknown. Using comprehensive and complementary approaches encompassing biochemical assays, super-resolution and immunogold transmission electron microscopy, we demonstrate that Cx43 localizes to the nuclear envelope of different cell types and in cardiac tissue. We show that translocation of Cx43 to the nucleus relies on Importin-β, and that Cx43 significantly impacts the cellular transcriptome, likely by interacting with transcriptional regulators. In vitro patch-clamp recordings from HEK293 and adult primary cardiomyocytes demonstrate that Cx43 forms active channels at the nuclear envelope, providing evidence that Cx43 can participate in nucleocytoplasmic shuttling of small molecules. The accumulation of nuclear Cx43 during myogenic differentiation of cardiomyoblasts is suggested to modulate expression of genes implicated in this process. Altogether, our study provides new evidence for further defining the biological roles of nuclear Cx43, namely in cardiac pathophysiology.

Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions

“…Hemichannels can also function independently in nonjunctional areas, mediating the exchange of molecules across the plasma membrane (Figure 2iii). Additionally, connexins can influence gene expression, cellular migration, and other molecular mechanisms by localizing to the cytoplasm and the nucleus without forming channels on the plasma membrane (Kotini et al, 2018;Martins-Marques et al, 2023). Connexins have a short half-life and the turnover of the hemichannels and GJs, which is mediated by endocytosis at the plasma membrane, enables cells to rapidly respond to environmental changes (Figure 2) (VanSlyke and Musil, 2005;Falk et al, 2016;Aasen et al, 2019).…”