Protein–Protein Interactions with Connexin 43: Regulation and Function

Abstract

Connexins are integral membrane building blocks that form gap junctions, enabling direct cytoplasmic exchange of ions and low-molecular-mass metabolites between adjacent cells. In the heart, gap junctions mediate the propagation of cardiac action potentials and the maintenance of a regular beating rhythm. A number of connexin interacting proteins have been described and are known gap junction regulators either through direct effects (e.g., kinases) or the formation of larger multifunctional complexes (e.g., cytoskeleton scaffold proteins). Most connexin partners can be categorized as either proteins promoting coupling by stimulating forward trafficking and channel opening or inhibiting coupling by inducing channel closure, internalization, and degradation. While some interactions have only been implied through co-localization using immunohistochemistry, others have been confirmed by biophysical methods that allow detection of a direct interaction. Our understanding of these interactions is, by far, most well developed for connexin 43 (Cx43) and the scope of this review is to summarize our current knowledge of their functional and regulatory roles. The significance of these interactions is further exemplified by demonstrating their importance at the intercalated disc, a major hub for Cx43 regulation and Cx43 mediated effects.

Connexin 43 maintains tissue polarity and regulates mitotic spindle orientation in the breast epithelium

“…We speculate that the interaction between Cx43 junctional complex and tight junction ZO proteins, or with molecules like Par3 that are involved in the PI3K-AKT pathway controlling MSO (Tenvooren et al, 2019), might underlie Cx43mediated MSO. It is unlikely that Cx43 exerts an impact on MSO via its known interaction with tubulin (Sorgen et al, 2018;Vanderpuye et al, 2016), since we rarely observed Cx43 localized near the mitotic spindle (Fig. S6C).…”

Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications

“…Moreover, connexin-based channels at the plasma membrane that are not assembled into gap junctions, also known as hemichannels, have central roles in autocrine and paracrine signaling by providing a pathway for the exchange of ions and small molecules between the intracellular and extracellular milieus [7]. In addition, the intracellular domains of connexins can interact with other proteins, including components of the cytoskeleton, such as tubulin, and cell signaling pathways, such as cyclin E and β-catenin [8][9][10][11]. Through such protein-protein interactions, connexins can modulate cell growth, differentiation, migration and other cellular processes in channel-independent manners.…”

Small G protein signaling modulator 3 (SGSM3) knockdown attenuates apoptosis and cardiogenic differentiation in rat mesenchymal stem cells exposed to hypoxia

“…induces its degradation, and these results suggest that SGSM3 may induce Cx43 turnover through the lysosomal pathway [34]. The Cx43 is affected by interactions between Cx43 and numerous proteins, which related to trafficking, channel construction, and degradation [35,36]. SGSM3 increases Cx43 turnover by accelerating the internalization of Cx43 from the plasma membrane [37].…”