Managing the complexity of communication: regulation of gap junctions by post-translational modification

Abstract

Gap junctions are comprised of connexins that form cell-to-cell channels which couple neighboring cells to accommodate the exchange of information. The need for communication does, however, change over time and therefore must be tightly controlled. Although the regulation of connexin protein expression by transcription and translation is of great importance, the trafficking, channel activity and degradation are also under tight control. The function of connexins can be regulated by several post translational modifications, which affect numerous parameters; including number of channels, open probability, single channel conductance or selectivity. The most extensively investigated post translational modifications are phosphorylations, which have been documented in all mammalian connexins. Besides phosphorylations, some connexins are known to be ubiquitinated, SUMOylated, nitrosylated, hydroxylated, acetylated, methylated, and γ-carboxyglutamated. The aim of the present review is to summarize our current knowledge of post translational regulation of the connexin family of proteins.

Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells

“…Our study thus provides one of the first observations that MAPKs can be activated also by the parental chemicals via rapid signaling mechanisms. Although MAPKs have been implicated in the regulation of GJIC via Cx43 phosphorylation (Axelsen et al, 2013), Cx43 phosphorylation followed by its internalization was observed only for VIN but not MXC. Moreover, neither MXC -nor VIN -induced inhibition of GJIC was prevented by a MEK1/2 inhibitor, which indicates that dysregulation of GJIC by these 2 chemicals did not occur via classical ERK1/2-dependent mechanism reported for TPA, EGF, or lindane (Sovadinova et al, 2015).…”

“…Exchange of various ions, nutrients, secondary messengers or microRNAs through gap junctional connexin channels represents a key mechanism required for coordination of signal transduction pathways and control of gene expression within a tissue, which is essential for proper tissue development, function and regeneration (Trosko, 2011). GJIC is a process strictly regulated via transcriptional, translational, post-translational and epigenetic mechanisms (Axelsen et al, 2013;Vinken et al, 2009a,b). These non-endocrine dependent mechanisms might be involved in VIN and MXC induced increases in liver hypertrophy and hepatocellular carcinomas in various rodent model systems (HSDB, 2010;Reuber, 1980).…”

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias

“…For a detailed review, see Dhein (2004); Salameh and Dhein (2005); Axelsen et al (2013). Channel conductance depends on the connexin isoform, the phosphorylation state of the connexin, and on the connexin composition of the channel (e.g., homomeric, heteromeric) (Harris, 2001; Moreno, 2004).…”

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias

“…For a detailed review, see Dhein (2004); Salameh and Dhein (2005); Axelsen et al (2013). Channel conductance depends on the connexin isoform, the phosphorylation state of the connexin, and on the connexin composition of the channel (e.g., homomeric, heteromeric) (Harris, 2001;Moreno, 2004).…”