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1.A.24 The Gap Junction-forming Connexin (Connexin) Family

Gap junctions, found in the plasma membranes of vertebrate animal cells, consist of clusters of closely packed pairs of transmembrane channels, the connexons, through which small molecules diffuse between neighboring cells (Zhou and Jiang 2014). The connexons consist of homo- or heterohexameric arrays of connexins (Cxs), and the connexon in one plasma membrane docks end-to-end with a connexon in the membrane of a closely opposed cell. The hemichannel is made of six connexin subunits (Kar et al., 2012). The properties and possible functions of unpaired connexin and pannexin hemichannels and the implications this has for a variety of events, such as cell death, glutamate release, oxidative stress, cortical spreading depression, that occur during an ischemic insult and may affect its outcome, have been reviewed (Bargiotas et al. 2009). The two connexons are docked by interdigitated, anti-parallel beta strands across the extracellular gap. The second extracellular loop guides selectivity in docking between connexons formed by different isoforms (Kovacs et al. 2007). There is considerably more sequence variability of the N-terminal portion of E2; possibly this region dictates connexon coupling.  Structure/function relationships for connexins have been reviewed (Beyer and Berthoud 2017). The roles of connexin hemichannels in normal cochlear function and in promoting hearing loss have been reviewed (Verselis 2017). Connexin-mediated cell communication in the kidney presents a potential therapeutic target for intervention of diabetic kidney disease (Price et al. 2020). Both connexins and pannexins contribute to the induction and spreading of orofacial pain (Li et al. 2020). Cxs may play a role in preeclampsia, and ROS and RNS may alter Cxs-formed channels (Rozas-Villanueva et al. 2020). Connexins have been linked to cancers, cardiac and brain disorders, chronic lung and kidney conditions and wound healing processes (Nalewajska et al. 2020). Gap junction liposomes have been used for efficient delivery of chemotherapeutics to solid tumors (Trementozzi et al. 2020). Connexins may play a role in spinal cord injury, and Cx-specific inhibitors that may be useful for treatment are known (Abou-Mrad et al. 2020). Over-activated hemichannels may be targets for drugs treating human diseases (Retamal et al. 2021). In fact, screens for inhibitors of Cx43 hemichannel function have revealed several candidates (Soleilhac et al. 2021). Endothelial cell Cxs regulate physiological and pathological angiogenesis through canonical and noncanonical functions (Haefliger et al. 2022). Ca2+-dependent and Ca2+-independent calmodulin binding to the cytoplasmic loop of gap junction connexins has been described (Tran et al. 2023).

Over 15 connexin subunit isoforms are known. They vary in size between about 25 kDa and 60 kDa. They have four putative transmembrane α-helical spanners, and direct experimental evidence favors the α-helical folding of at least two of these TMSs. Connexins are similar in sequence and are designated connexins α1-8 and β1-6. Low resolution structural data are available for a gap junction membrane channel. A dodecameric channel is formed by the end-to-end docking of two hexamers, each displaying 24 TMSs (4 α-helical TMSs per connexin subunit) (Bosco et al., 2011). Gap junctional channels are parts of multiprotein complexes (Hervé et al., 2011).  Regulation of cardiovascular connexins have been reviewed (Meens et al. 2013). The proteins interacting with Cx43, the most prevalent connexin (TC# 1.A.24.1.1; the rat and human orthologs are 98 % identical), include: c-Src (TC#1.A.23.1.12; P12931), ZO-1 (8.A.24.1.9; Q07157), drebrin (TC#; DBN1; Q16643), CIP85 (TC# 8.A.87.1.5; Q96HU1) and CCN3 (8.A.87.1.6; P48745), as well as feedback between gap junctions, adherens junctions (N-cadherin and catenins) and the cytoskeleton (microtubules and actin) (Giepmans 2006). Genome-wide characterization of gap junction (connexin and pannexin) genes in turbot (Scophthalmus maximus L.) with respect to evolution and immune response following Vibrio anguillarum infection has been published (Cai et al. 2022). Connexins and pannexins connect the external environment with the cytoplasm of the cell, but only connexins are able to link two cells together, allowing transport from one cell to another (Roterman et al. 2022).

Connexin channels have been reconstituted in unilamellar phospholipid vesicles from purified rat liver connexin 43. The vesicles were shown to be permeable to sucrose and the dye, lucifer yellow, and channel activity was reversibly inhibited by phosphorylation of connexin 43 by mitogen-activated protein (MAP) kinase. Other kinases may also effect inhibition. Gating of connexin 43 channels may therefore be regulated by phosphorylation of the connexin subunit in vivo. However, the cytoplasmic tails differ considerably in the size and amino acid sequence for different connexins and are predicted to be involved in the channel open and closed conformations. A ball and chain model for hemichannel conformational changes has been proposed for some connexins (e.g., Cx43) with large cytoplasmic tails (Liu et al., 2006). The tail folds into a ball or 'gating particle' and binds to the cytoplasmic loop domain, leading to channel closure (Liu et al., 2006). The involvement of lymphatic connexins and pannexins in health and disease has been reviewed (Ehrlich et al. 2021). Ephaptic coupling is a mechanism of conduction reserve during reduced gap junction coupling (Lin et al. 2022). Pannexin1, Connexin32, and Connexin43 in spotted sea bass (Lateolabrax maculatus are important neuro-related immune response genes involved in inflammation-induced ATP release (Sun et al. 2022). The role of ATP release through connexin hemichannels during neurulation has been discussed (Tovar et al. 2023).

Different connexins may exhibit differing specificities for solutes. For example, adenosine passed about 12-fold better through channels formed by Cx32 while AMP and ADP passed about 8-fold better, and ATP greater than 300-fold better, through channels formed by Cx43. Thus, addition of phosphate to adenosine appears to shift its relative permeability from channels formed by Cx32 to channels formed by Cx43. This may have functional consequence because the energy status of a cell could be controlled via connexin expression and channel formation (Goldberg et al., 2002). The relationship between redox signaling and Cxs has shown that redox signaling molecules (e.g., hydrogen peroxide (H2O2) and nitric oxide (NO)) affect Cxs-based channel function while the opening of Cx channels also triggers the transfer of various redox-related metabolites (e.g., reactive oxygen species, glutathione, nicotinamide adenine dinucleotide and NO). On the basis of this evidence, Zhang et al. 2021 proposed the existence of redox-Cxs crosstalk. Connexin hemichannels are candidate targets for cardioprotective and anti-arrhythmic treatments (Leybaert et al. 2023).

Connexin channels allow the passage of ions and other biomolecules smaller than ~ 1 kDa, thereby synchronizing the cells both electrically and metabolically. Cxs are expressed in all retinal cell types, and the diversity of Cx isoforms involved in the assembly of the channels provides a functional syncytium required for visual transduction. Ponce-Mora et al. 2023 summarized the knowledge regarding Cx biology in retinal tissues and discuss how Cx dysfunction is associated with retinal disease pathophysiology. Although the contribution of Cx deficiency to retinal degeneration is not well understood, recent findings present Cx as a potential therapeutic target.  Gap junction mediated bioelectric coordination is required for slow muscle development, organization, and function (Lukowicz-Bedford et al. 2023).

There are about 20 isoforms of connexin proteins, each forming channels with distinct channel properties (Ayad et al., 2006). Moreover, connexins can form both homomeric and heteromeric connexin channels. Two homomeric channels may have different permeability properties that differ from those of the heteromeric channels including both proteins (see 1.A.24.1.3; Ayad et al., 2006). Connexin23 has only 4 conserved cysteines in the extracellular domain, but they still form hemichannels (Iovine et al., 2008)  A robust and updated classification of the human 4 TMS protein complement has appeared (Attwood et al. 2016). The connexin gene family is under extensive regulation at the transcriptional and post-transcriptional levels, and they undergoes numerous modifications at the protein level, including phosphorylation, which ultimately affects their trafficking, stability, and function (Aasen et al. 2018). Cx26, Cx32, and Cx43 proteins are present in human labial salivary gland biopsies (hLSGBs) in the duct and acinar cells, as well as in myoepithelial cells (Falleni et al. 2022). Gap juntional proteins, connexins and pannexins, interact with tight junctions, adhesive junctions, and cell adhesions to form a complex network that participates in cell-cell junctional organization, ATP binding, ion channel, and voltage-gated conduction (Liu et al. 2023).

Deletion or mutation of the various connexin isoforms produces distinctive phenotypes and pathologies. This observation reflects (1) the different molecular specificities, (2) the different relative magnitudes of transport rates of various compounds via these channels, and (3) the regulatory properties via these dissimilar channels.  Genetic diseases indicate that the normal function of CNS myelin depends on connexin32 (Cx32) and Cx47, gap junction (GJ) proteins expressed by oligodendrocytes. GJs couple oligodendrocytes to themselves (O/O channels), astrocytes to themselves (A/A channels), and oligodendrocytes to astrocytes (O/A channels). Astrocytes and oligodendrocytes express different connexins. Cx47/Cx43 and Cx32/Cx30 efficiently form functional channels, but neither Cx47 nor Cx43 formed channels with Cx30 or Cx32 (Orthoann-Murphy et al., 2007). Cx47/Cx43 and Cx32/Cx30 channels have distinct properties and permeabilities. Cx47 mutants that cause Pelizaeus-Merzbacher-like disease do not efficiently form functional channels with Cx43, indicating that disrupted Cx47/Cx43 channels cause this disease.  The mutations in connexins that give rise to disease have been summarized and discussed (Pfenniger et al. 2011).  While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease (Molica et al. 2014).

Maeda et al. (2009) have reported the crystal structure of the gap junction channel formed by human connexin 26 (Cx26, also known as GJB2) at 3.5 Å resolution. The density map showed the two membrane-spanning hemichannels and the arrangement of the four transmembrane helices of the six protomers forming each hemichannel. The hemichannels feature a postively charged cytoplasmic entrance, a funnel, a negatively charged transmembrane pathway, and an extracellular cavity. The pore is narrowed at the funnel, which is formed by the six amino-terminal helices lining the wall of the channel, which thus determines the molecular size restriction at the channel entrance. The structure of the Cx26 gap junction channel also has implications for the gating of the channel by the transjunctional voltage (Nakagawa et al., 2010). The N-terminal half of connexin 46 appears to contain the core elements of the pore and voltage gates (Kronengold et al., 2012). 

Research has revealed a multilevel platform via which connexins (Cxs) and pannexins (Panxs) can influence the following cellular functions within a tissue: (1) Cx gap junctional channels (GJCs) enable direct cell-cell communication of small molecules, (2) Cx hemichannels and Panx channels can contribute to autocrine/paracrine signaling pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as cell-cell adhesion, interactions with the cytoskeleton, and the activation of intracellular signaling pathways. Decrock et al. 2015 discuss their multifaceted contributions to brain development and specific processes in the NGVU, including synaptic transmission and plasticity, glial signaling, vasomotor control, and blood-brain barrier integrity in the mature CNS. Connectosomes, cell-derived lipid vesicles that contain functional gap junction channels and encapsulate molecular cargos, have been used to deliver cargos such as drugs into the cytoplasm of a cell (Gadok et al. 2016).

Connexins (Cx) contain both highly ordered domains (i.e., 4 transmembrane domains) and primarily unstructured regions (i.e., N- and C-terminal domains). The C-terminal domains vary in length and amino acid composition from the shortest on Cx26 to the longest on Cx43. With the exception of Cx26, the C-terminal domains contain multiple sites for posttranslational modification (PTM) including serines (S), threonines (T), and tyrosines (Y) for phosphorylation as well as cysteines (C) for S-nitrosylation. These PTMs are critical for regulating cellular localization, protein-protein interactions, and channel functionality (Lohman et al. 2016).  The latest advances in the channel-dependent and independent roles of connexins in fibrosis, the EMT, and wound healing hae been reviewed. (Li et al. 2023).

Fatty acids (FAs) have effects on connexin- and pannexin-based channels. FAs regulate diverse cellular functions, including the activities of connexin (Cx) and Panx channels which form hexameric hemichannels (HCs), which assemble into dodecameric gap junction channels (GJCs).  It has been shown that FAs decrease GJC-mediated cell-cell communication. Changes in GJCs mediated by FAs have been associated with post-translational modifications (e.g., phosphorylation), and seem to be directly related to chemical properties of FAs (Puebla et al. 2017). 

Connexins participate in the generation of intercellular calcium waves, in which calcium-mediated signaling responses spread to contiguous cells through gap junction to transmit calcium signaling throughout the airway epithelium. Pannexins in the nasal mucosa contribute not only to ciliary beat modulation via ATP release, but also regulation of mucus blanket components via H2O efflux. The synchronized roles of pannexin and connexin may allow effective mucociliary clearance in nasal mucosa (Ohbuchi and Suzuki 2018).

Gadok et al. 2016 have developed 'connectosomes', cell-derived lipid vesicles that contain functional gap junction channels and encapsulate molecular cargos. They showed that these vesicles form gap junctions with cells, opening a direct and efficient route for the delivery of molecular cargo to the cellular cytoplasm. Specifically, they demonstrated that using gap junctions to deliver doxorubicin reduces the therapeutically effective dose of the drug by more than an order of magnitude (Gadok et al. 2016).  Single-domain antibodies on connectosomes allows gap junction-mediated drug targetting to specific cell types (Gadok et al. 2018). An overview of connexin biology, including their synthesis and degradation, their regulation and interactions, and their involvement in cardiac pathophysiology, including their involvement in myocardial ischemia/reperfusion injury, cardiac fibrosis, gene transcription and signaling regulation have been reviewed (Rodríguez-Sinovas et al. 2021).

Connexins have been implicated in cancer biology for their context-dependent roles that can either promote or suppress cancer cell functions. They are able to modulate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules (Jones and Bodenstine 2022). During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance (Jones and Bodenstine 2022).

The transport reaction catalyzed by connexin gap junctions is:

Small molecules (cell 1 cytoplasm)  Small molecules (cell 2 cytoplasm)

Small molecules include small proteins, cyclic nucleotides, chemotherapeutics and small RNAs.

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