Gap junctional channels are parts of multiprotein complexes

Abstract

Gap junctional channels are a class of membrane channels composed of transmembrane channel-forming integral membrane proteins termed connexins, innexins or pannexins that mediate direct cell-to-cell or cell-to extracellular medium communication in almost all animal tissues. The activity of these channels is tightly regulated, particularly by intramolecular modifications as phosphorylations of proteins and via the formation of multiprotein complexes where pore-forming subunits bind to auxiliary channel subunits and associate with scaffolding proteins that play essential roles in channel localization and activity. Scaffolding proteins link signaling enzymes, substrates, and potential effectors (such as channels) into multiprotein signaling complexes that may be anchored to the cytoskeleton. Protein-protein interactions play essential roles in channel localization and activity and, besides their cell-to-cell channel-forming functions, gap junctional proteins now appear involved in different cellular functions (e.g. transcriptional and cytoskeletal regulations). The present review summarizes the recent progress regarding the proteins capable of interacting with junctional proteins and highlights the function of these protein-protein interactions in cell physiology and aberrant function in diseases. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions.

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

“…Indeed, it was reported in various cell types that the absence of Cx43 leads to a differential cellular transcriptome, which ultimately determines phenotyp- ical changes in cell morphology and cell adhesion suggesting that Cx43 has a direct role on gene transcription (6). On the other hand, studies carried out in osteosarcoma cell lines and in mouse bone marrow stromal cells (BMSCs), have shown that defects in GJIC may alter the subcellular localization and the recruitment of transcription factors to the promoter region of certain genes, impacting upon gene transcription (52,53).…”

High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

“…Connexins mediate intercellular communication through gap junction channels formed by two connexons that connect adjacent cells or as unopposed hemichannels, via the release of small molecules to the extracellular medium (2). The C terminus of connexin proteins faces the cytoplasm and through interactions with kinases and structural molecules participate in the regulation of intracellular signaling independently of channel activity (3).…”

The Carboxyl Tail of Connexin32 Regulates Gap Junction Assembly in Human Prostate and Pancreatic Cancer Cells

“…The cytoplasmic tails of many Cxs have also been shown to interact directly or indirectly with several proteins (10). Although these interactions have been postulated to control the assembly of Cxs into gap junctions, the molecular mechanisms involved have remained unexplored (10). In particular, it is not clear what the exact role of a Cx cytoplasmic tail is and at which step it is involved in regulating the assembly of gap junctions.…”

“…The role of the two extracellular loop domains of Cxs in the formation of cell-to-cell channels as well as of the cytoplasmic tails in regulating the opening and closing of cell-cell channels has been well documented (5,(7)(8)(9). The cytoplasmic tails of many Cxs have also been shown to interact directly or indirectly with several proteins (10). Although these interactions have been postulated to control the assembly of Cxs into gap junctions, the molecular mechanisms involved have remained unexplored (10).…”

“…In particular, it is not clear what the exact role of a Cx cytoplasmic tail is and at which step it is involved in regulating the assembly of gap junctions. For example, the interaction of a scaffolding protein, ZO-1, which binds to the PDZ-binding domain of several Cxs, facilitates the assembly of Cx43, an ubiquitously expressed Cx, into gap junctions (11,12) yet has an opposite effect on the assembly of Cx50, which is expressed in lens epithelial cells (10,13). Thus, it is highly likely that besides ZO-1, other proteins documented to interact with Cxs might inhibit or enhance gap junction assembly and disassembly in a tissue-specific and cell-context-dependent manner.…”