Posttranslational Modifications in Connexins and Pannexins

Abstract

Post-translational modifications are a common cellular process that is used by cells to ensure a particular protein function. This can happen in a variety of ways, for example from the addition of phosphates or sugar residues to a particular amino acid ensuring proper protein life cycle and function. In this review, we assess evidence for ubiquitination, glycosylation, phosphorylation, S-nitrosylation as well as other modifications on connexins and pannexin proteins. Based on the literature, we find that post-translational modifications are an important component of connexin and pannexin regulation.

Diverse post-translational modifications of the pannexin family of channel-forming proteins

“…27 With the notable exception of the S-palmitoylation of Panx2 in stem-like neural progenitor cells, 28 our knowledge of the post-translational modifications of the other 2 pannexins is restricted to the evidence that they are N-linked glycoproteins. Protein glycosylation plays a crucial role in many key biological processes such as cell-cell interactions, adhesion, signal transduction, and recognition.…”

“…29 Consequently, this and other posttranslational modifications may be important for the regulation of pannexin channels as has been well documented for other ion channels and connexin channels modulated by phosphorylation, palmitoylation, S-nitrosylation, and SUMOylation. 27 Most tissues express at least 2 pannexin isoforms that could, in some instances, functionally compensate for each other, particularly if they are differentially regulated by posttranslational modifications. Among the 3 pannexins, we have previously reported that sequence homology is highest between Panx1 and Panx3 (41% identical/59% conserved), 6 particularly in the transmembrane domains of the 2 isoforms.…”

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…It has become increasingly evident that the C-terminal region of Cx43 acts as a binding domain for many molecules that are involved in its trafficking, membrane stability, and gap junctional communications (Niger et al, 2010) (see section III.A.1). The C terminus is an unstructured, highly dynamic region that contains multiple sites for posttranslational modifications, including phosphorylation, nitrosylation, palmitoylation, sumoylation, and ubiquitination (Palatinus et al, 2011b;Straub et al, 2011;Johnstone et al, 2012a;Chen et al, 2013). As described in section III.A.1, the connexin C terminus is primarily unfolded and rich in serine, threonine, and tyrosine residues (Ser/Thr/Tyr) that are targeted for posttranslational modifications (Solan et al, 2003(Solan et al, , 2009Chen et al, 2013).…”

“…Additionally, through a number of techniques including coimmunoprecipitation, immunofluorescence overlap, and pull-down assays, direct interactions have been identified within the Cx43 C terminus, with the suggestion that this can reduce the signaling properties of the gap junctional pore (Niger et al, 2010). Kinases and sites within Cx43 have been well characterized, including phosphorylation by kinases from the src family of Tyr265, and phosphorylated by MAPK of Ser255/(Ser262)/Ser279/ Ser282 residues (Solan and Lampe, 2009;Johnstone et al, 2012a;Chen et al, 2013). Presumptively, these posttranslational modifications induce structural changes within the connexin C-terminal region that allow for further protein interactions with this region (Saidi Brikci-Nigassa et al, 2012).…”

Carbon Monoxide (CO) Is a Novel Inhibitor of Connexin Hemichannels

“…Phosphorylation (12), protease cleavage (13), and membrane potential (14) are well known factors. Recently, it has been proposed that changes in redox potential are also important modulators of Cx43 and Cx46 HCs (11,15); for example, nitric oxide (NO) induces the S-nitrosylation of Cx43 intracellular Cys and causes HC opening (11).…”