Gap Junction Signaling


Pathway Description

Gap junction channels span two plasma membranes and are formed by the alignment of two hemichannels, each consisting of an oligomer of structural subunit proteins called Connexins (Cx). These junctional proteins constitute a multigene family whose members are distinguished according to their predicted molecular weight. A connexin structure consists of two extracellular loops, four membrane-spanning domains, one cytoplasmic loop, one N-terminal tail, and one C-terminal tail. During intercellular channel formation, six connexins oligomerize into a connexon or hemichannel that docks in homotypic, heterotypic and combined heterotypic/heteromeric arrangements. In total, as many as 14 different connexon arrangements can be formed when two members of the connexin family intermix. This is followed by connexon trafficking to the plasma membrane. The intact channel is formed when one hemichannel docks with a second in an opposing cell. Once assembled, groups of these intercellular channels (termed gap junctional plaques) mediate the passage of amino acids, second messengers, ions and other metabolites between the connected cytoplasmic domains.Connexin-43 is the most ubiquitously expressed of the connexins. It is endogenously expressed in at least 35 distinct tissues encompassing over 35 cell types that include cardiomyocytes, keratinocytes, astrocytes, endothelial cells and smooth-muscle cells among many others. It co-oligomerizes with other connexins such as Cx26 (keratinocytes and hepatocytes), Cx31 (keratinocytes and myocardium) and Cx46 (trans-Golgi network). However, it is unable to co-oligomerize with Cx32. Connexins also bind ZO-1 and ZO-2 at different stages of the cell cycle to regulate gap junction size and stability, interact directly with β-catenin to regulate gap-junctional intercellular cross-talk with WNT signaling (essential for cell survival), and regulate the turnover of Cx43-containing gap junctions, in turn stabilizing the junctions. The actin-binding protein Dbn-1 binds and links gap junctions to the sub-membrane cytoskeleton, whereas other cytoskeletal proteins such as Tubulin-α and β facilitate connexin-mediated transport.

Consisting of hundreds of intercellular channels, gap junctions are critically important in regulating embryonic development, excitable cell contraction, tissue homeostasis, apoptosis, metabolic transport and normal cell growth and differentiation. GJ communication is controlled by neurotransmitters such as Norepinephrine, Dopamine, Serotonin and Glutamate, cytokines, growth factors, and other bioactive compounds such as lysophosphatidic acid. These biomolecules activate downstream kinases leading to increased levels of phosphorylation at specific sites and opening and closing of the channel. Kinases such as PKG, PKA, PKC and ERK1/2 play a role in phosphorylation and acute gating of gap junction channels. Gap junctional communication also gets disrupted in response to extracellular cues such as growth factors which regulate post-translational phosphorylation of Cx43 and connexin redirection from the plasma membrane.