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Gap junctions and hemichannels: communicating cell death in neurodevelopment and disease Belousov, Andrei B; Fontes, Joseph D; Freitas-Andrade, Moises; Naus, Christian C Jan 17, 2017

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REVIEWGap junctions and hemichcommunicating cell deathdsseanwactions mediated by direct cell-cell contact in additioncessing as well as neuronal protection in the brain. Oneprobability of these channels, providing a mean of includingmade of six proteins called connexins [3]. Hemichannelsextracellulara multi-geneals [4].us cell typesg it a very di-ication. WithThe Author(s) BMC Cell Biology 2017, 18(Suppl 1):4DOI 10.1186/s12860-016-0120-xthree (Cx43, Cx30, Cx26), as do oligodendrocytes (Cx32,Mall, Vancouver, BC V6T 1Z3, CanadaFull list of author information is available at the end of the articleregard to the different cell types, neurons express sevendifferent connexins (see below), astrocytes express up to* Correspondence: christian.naus@ubc.ca3Department of Cellular & Physiological Sciences, Faculty of Medicine, LifeSciences Institute, The University of British Columbia, 2350 Health Sciencesjunctions (GJs), clusters of intercellular membrane chan-nels which provide for direct cytoplasmic continuitybetween adjacent cells [1].communicating between intracellular andcompartments. Connexins are encoded byfamily consisting of 20–21 members in mammWithin the mammalian brain, the varioexpress over ten different connexins, makinverse organ regarding intercellular communmechanism mediating such interactions involves gap can also function in their own right, having distinct roles into paracrine signaling (gliotransmission). Furthermore anumber of glial-neuronal interactions exist, and thesehave been implicated in both normal information pro-the channels in the general signaling and physiology of thecells and tissues. A single GJ channel consists of two oppos-ing hemichannels, also known as connexons, which areCx43 play critical roles in neurodevelopment. These connexins also mediate distinct aspects of the CNS response topathological conditions. An imbalance in the expression, translation, trafficking and turnover of connexins, as wellas mutations of connexins, can impact their function in the context of cell death in neurodevelopment and disease.With the ever-increasing understanding of connexins in the brain, therapeutic strategies could be developed totarget these membrane channels in various neurological disorders.BackgroundThe complexity of the mammalian central nervoussystem (CNS) is due in large part to the various celltypes from which it is composed, as well as the differentforms of cellular interactions. These include neuronalinteractions via neurotransmission, as well as glial inter-Gap junctions and connexins in the CNSGJs allow the passive intercellular diffusion of small mole-cules, such as glutamate, glutathione, glucose, adenosinetriphosphate (ATP), cyclic adenosine monophosphate(cAMP), inositol 1,4,5-trisphosphate (IP3), and ions (Ca2+,Na+, K+) [2]. In addition, cells are able to control the opentimepoints when they are expressed in the developing and mature CNS. Both the main neuronal Cx36 and glialneurodevelopment and dAndrei B. Belousov1, Joseph D. Fontes2, Moises Freitas-AnFrom International Gap Junction Conference 2015Valparaiso, Chile. 28 March - 2 April 2015AbstractGap junctions are unique membrane channels that play adeveloping and mature central nervous system (CNS). Theoligomerize into hexamers to form connexons or hemichCNS, with some specificity with regard to the cell types in© The Author(s). 2017 Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zeOpen Accessannels:iniseaserade3 and Christian C. Naus3*ignificant role in intercellular communication in thechannels are composed of connexin proteins thatnels. Many different connexins are expressed in thehich distinct connexins are found, as well as thele is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.The Author(s) BMC Cell Biology 2017, 18(Suppl 1):4 Page 2 of 11Cx29, Cx47), microglia (Cx43, Cx32, Cx36) and endo-thelial cells (Cx37, Cx40, Cx43) [5–7]. These channelshave distinct functions within the different cell types andtheir expression can change dramatically during neuro-development and injury (see below). GJs in oligodendro-cytes have been shown to be essential for propermyelination [8], as well as potassium buffering [9].Endothelial functions are closely regulated by junctionalinteractions with astrocytes; specifically important arethe connexins expressed in astrocytic endfeet [10, 11]. Inthis context, astrocytes and endothelial cells do not formgap junctions between them, but rather the connexin inastrocytic endfeet may solely function as hemichannels.Cx43 is the most highly expressed connexin in thebrain because it is involved in extensive GJ coupling(GJC) between astrocytes, the most abundant cell typein the brain. GJ communication is also critical for theproliferation and differentiation of neural stem cells [12].Although microglia have been reported to express Cx43and form GJs [13], others have not observed Cx43 im-munoreactivity in microglia [14, 15]; while anothergroup showed that Cx43 does not form GJs in microglia[16], rather it forms hemichannels [17].Connexins are expressed in both neurons and astro-cytes, and are regulated by numerous factors in healthyand pathological conditions. Neuronal GJs and astrocyticGJs are regulated during development and disease. How-ever, given the nature of the tripartite synapse, neuroglialinteractions must also be considered in this context ofsynaptic malfunction.Expression and regulation of neuronal connexins inneural development and adulthoodDuring development, neurons of the rodent CNS ex-press a number of different connexins. These includeCx36 [18–20], Cx30.2 [21], Cx31.1 [22], Cx40 [23], Cx45[24] and Cx50 and Cx57 in the retina [25]. This presum-ably reflects the diversity of neuronal cell types, express-ing a range of connexins, and/or varying functions ofthose connexins in the developing CNS. However,knockout of specifically Cx36 results in near completeloss of neuronal GJC in the mature CNS, indicating thatit is the primary neuronal connexin [26–29]. Cx36 invarious regions of rodent CNS, and Cx35 (the fishorthologue of Cx36) expressed in goldfish Mauthnercells, are often present in mixed chemical and electricalsynapses. Cx36 GJs have been observed in close proximityto α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidreceptors (AMPARs) [25, 30] as well as N–methyl–D–as-partate (NMDA) receptors (NMDARs) [30–32]. Multiplereports have demonstrated that Cx36 GJs can be tetheredto the cytoskeleton via complex formation with multipleintracellular proteins. Constituents of Cx36-interactingcomplexes include structural proteins, regulators ofchannel activity and gene transcription, as well as factorsinvolved in protein transport, assembly and localization[33–35]. Data suggest that Cx36 may bind these proteinssimultaneously at some GJs within the same neuron andthe binding requires a four amino acid motif (SAYV)present in the C-terminus of the Cx36 protein [34, 35].The interaction of Cx36 with these proteins appears to benecessary for addition into electrical synapses, since theSAYV motif is required for incorporation [36].Cx36 is phosphorylated and its activity is influencedby a number of kinases including cAMP-dependentprotein kinase (PKA), cGMP-dependent protein kinase,protein kinase C (PKC) and casein kinase II [37–39].Ca2+/calmodulin-dependent protein kinase II (CaMKII)interacts with and phosphorylates Cx36 in mouse infer-ior olive neurons and Cx35 in synapses of teleostMauthner cells [40, 41]. The binding of Cx36 to CaMKIImay not be limited to a substrate-enzyme interaction.Rather, there is some indication that the interaction isassociated with changes in expression and/or stability ofthe kinase. It is noteworthy that neurons of Cx36 knock-out mice have reduced CaMKII levels [42].Neuronal GJC is finely regulated among individualplaques (i.e., clusters of GJ channels). A given neuroncan be coupled to a variable number of neighboringneurons and display different degrees of conductancewith each of its coupled partners [32]. Similarly, bindingto CaMKII [40] and the phosphorylation status of Cx36[43] is not uniform within a neuron. Thus, the nature ofsignaling complexes associated with individual GJs pre-sumably facilitates the fine-tuning of individual synapsesand cell-type specific activity [43]. The interactions listedabove have also been reported for non-neuronal connex-ins (e.g., Cx43) suggesting that modulation of GJ activityby these interactions may be a general feature [44].Spatial and temporal variation in GJC during develop-ment of the mammalian CNS has been well documented[45–49]. The expression of Cx36 and associated GJC in-crease during the first two postnatal weeks in most rodentCNS regions (including the cortex and hypothalamus).This initial, relatively robust expression declines duringthe third and fourth postnatal weeks [18, 50, 51]. This isin contrast to other regions of the CNS, such as the spinalcord, where Cx36 expression and coupling is highestduring the late embryonic period followed by a decline inthe first postnatal days [18, 52, 53]. The developmentaldecline in GJC is paired with changes in localization ofCx36 GJs to specific neuronal subtypes in the matureCNS [54, 55]. In the developing CNS in rodents, GJC isobserved between disparate neurons; glutamatergiccells (including pyramidal cells) were found to couplewith interneurons [20, 56] and neurons may couplewith glial cells [57]. However, in the mature CNS, Cx36GJs are found mostly between GABAergic interneuronsThe Author(s) BMC Cell Biology 2017, 18(Suppl 1):4 Page 3 of 11(GABA, γ-aminobutyric acid). It should be noted thatconnexins other than Cx36 also form GJs in the devel-oping CNS [23, 58].Despite the fact that chemical synaptic transmission isabsent while Cx36 expression initiates in development[59], chemical neurotransmitter receptors regulate thedevelopmental expression of neuronal GJC. In the ratand mouse hypothalamus and cortex, Cx36 expression isup-regulated by chronic activation of group II metabo-tropic glutamate receptors (mGluRs) and involvescAMP/PKA-dependent pathways. Conversely, GABAAreceptor activation blocks the developmental increase inCx36 expression [51] and is dependent upon develop-mental depolarization and Ca2+/PKC-dependent signals.The developmental programs of Cx36 expression areexecuted using transcriptional (up-regulation) and trans-lational (down-regulation) regulatory mechanisms [51].These multiple mechanisms contributing to the develop-mental expression of Cx36 and formation of GJC likelyexplain the interregional differences in the developmen-tal timing of GJC. The magnitude of the effects ofneurotransmitter pathways on Cx36 expression suggestsa modulatory rather than a definitive role in develop-mental regulation of neuronal GJC, primarily during theperiod when both electrical and chemical synaptic path-ways are being laid down.Regulation of Cx36 and GJC in the mature CNS occursas well. It allows rapid modification of neuronal connectiv-ity and signaling, including modulation of channel openingprobability and alterations in connexin protein homeosta-sis. Similar to developmental regulation, these regulatorymechanisms are influenced by neurotransmitter signaling.For example, activation of D1 and D2 dopamine receptors,serotonin (5-HT2) receptors, β-adrenoreceptors and eleva-tion of nitric oxide reduces dye coupling between ratcortical neurons within minutes [60]. Similarly, activationof β-adrenoreceptors decreases electrotonic couplingbetween rat hippocampal interneurons [61] and nitricoxide uncouples striatal neurons [62]. Activation of groupII mGluRs in developing mouse cortical neurons induced arapid increase followed by a decrease in Cx36 protein overa 24-h time period; Cx36 mRNA levels were unchangedduring this time, suggesting regulation of protein homeo-stasis [63]. However, whether Cx36 channel opening prob-ability is regulated in developing neurons is not yet known.The activity and regulation of Cx36 and GJC in neuronalinjury and cell deathEvery region of the mature CNS expresses Cx36 and hasGJs, though at levels below that observed during develop-ment [54]. Transient elevation of Cx36 and GJC occursfollowing a wide range of neuronal insults, includingischemia [64–66], spinal cord injury and traumatic braininjury (TBI) [67–69], retinal injury [70], epilepsy [71, 72]and inflammation [73]. The up-regulation of Cx36 andGJs in neurons following injury is very rapid, occurring1–2 h post-injury with a decline in the subsequent 24–48 h [66, 68, 69, 72, 73]. This is in stark contrast to thedevelopmental expression program outlined earlier,which occurs on the timescale of weeks; this differencein timing suggests that disparate regulatory mecha-nisms may be operating in development versus injury.The regulation of GJC expression and activity duringneuronal injury is a potential therapeutic target for redu-cing post-injury neuronal death. Rapid upregulation ofneuronal GJC and Cx36 expression was observed follow-ing multiple types of neuronal injury in adult mice [66]and coincides with the period of massive glutamaterelease from injured cells [74, 75]. The post-injury eleva-tion in coupling and Cx36 was prevented by blockade ofgroup II mGluRs and involves post-transcriptionalmechanisms since no change in Cx36 mRNA levels wereobserved [66]. In contrast to what was observed duringdevelopmental regulation, GABAA receptors were foundto be only indirectly involved in reducing Cx36 expressionafter injury, likely via inhibition of electrical activity. Giventhat neuronal GJC has been shown to be, predominantly,pro-death for neurons following injury (see below),manipulation of pathways that modify expression of Cx36might be a strategy for neuroprotection.The morbidity and mortality of stroke is a direct resultof neuronal death due primarily to ischemic injury andnecrosis [76–79]. Contributing to this is excessive glu-tamate release from ischemic cells producing NMDAR-mediated excitotoxicity and apoptosis [80–82]. Multipletypes of CNS insult beyond stroke, including TBI, epi-lepsy and inflammation, can produce significant neur-onal death, which also involves, in part, NMDARexcitotoxicity [80, 83–86]. While studies have reported arole for GJs in cell death and survival during glutamate-mediated excitotoxicity and neuronal injury, theirpredominant association has been with cell death.A few specific studies have reported a “pro-survival” roleof Cx36 and GJC. For example, pharmacological blockadeof GJs, using non-specific agents, augmented glutamate-induced neuronal death in mouse neuronal corticalcultures [87]. Similarly, secondary neuronal loss in themouse retina, following infrared laser photocoagulationwas most prominent 24–48 h post-injury, was increasedby GJ blockade (using non-selective and relativelyselective blockers for Cx36) and in Cx36 knockoutmice [70]. Both studies support the notion that GJCcontributes to cell survival.The preponderance of reports, however, indicates thatCx36 GJC promotes neuronal death, independent ofinitiating injury. As noted earlier, sustained activation ofgroup II mGluRs increased neuronal GJC and Cx36expression during development; this increase amplifiedThe Author(s) BMC Cell Biology 2017, 18(Suppl 1):4 Page 4 of 11NMDAR-mediated excitotoxicity. Consistent with this,blockade of group II mGluRs prevented increased Cx36 ex-pression and dampened neuronal death from excitotoxicity.These findings support a model where group II mGluRsregulate the developmental program of Cx36 GJC and bydoing so, contribute significantly to death decisions indeveloping neurons [51]. Group II mGluR activation medi-ates injury-associated increases in neuronal GJC. Notsurprisingly, blockade of group II mGluRs reduced injury-mediated neuronal death in multiple injury models [66, 88].Systemic administration of NMDA induced NMDAR-mediated excitotoxicity in the forebrain of adult wild-type mice, which was prevented by co-administration ofthe GJC blocker mefloquine [89]. Similarly, blockade ofGJC by mefloquine significantly reduced ischemic neur-onal death [89] and secondary neuronal death fromcontrolled cortical impact in mice (a model of TBI) [88].Cx36 knockout provided the same reduction in neuronaldeath in both models as pharmacological blockade.Mefloquine did not provide additional survival benefit inCx36 knockouts, suggesting the drug is working primar-ily through inhibition of Cx36 GJs [88, 89]. Additionalstudies also reported a pro-death role for neuronal GJCin NMDAR-mediated excitotoxicity and injury models[90–93]. From this and other work, a model ofglutamate-mediated excitotoxicity centered on neuronalGJs as the primary determinant of magnitude of thesecondary neuronal death following injury has been pro-posed [94, 95]. Despite the difficulty of making broadgeneralizations about the role of GJC in cell death,particularly in non-neuronal tissues [96, 97], blockade ofGJC as a strategy to limit neuronal death following stroke,TBI or other insult remains very attractive.Mechanisms by which neuronal Cx36 and GJC contributeto neuronal death and survivalUnderstanding how neuronal GJs contribute to celldeath and survival is critical, if manipulation of GJC isused as an approach to reduce neuronal damage anddeath in a variety of neurological diseases. Although,some of the studies discussed below were conductedwith the use of non-neuronal cells, they provided animportant information, which potentially may be applic-able to neurons too.Based upon numerous observations of passage of chem-ical substances via GJ channels, it has been proposed thatthe contributions of GJs to cell death and survival are bypropagation between the coupled cells of, respectively,“pro-death” and “pro-survival” GJ-permeable signals[98–100]. Though the identity of these signals remains ob-scure, signaling molecules such as IP3 and reactive oxygenand nitrogen species have been proposed as “pro-death”signals [100–102]. Conversely, molecules such as those in-volved in energy homeostasis (glucose and ATP), and freeradical scavengers (ascorbic acid and reduced glutathione)may be GJ-permeable “pro-survival” signals [96, 103]. Re-cently, a study was conducted in cultured neurons ob-tained from Cx36 knockout mice, in which the neuronswere transduced with lentiviral vectors expressing one ofthree wild-type connexins, including neuronal Cx36 andnon-neuronal Cx43 and Cx31 [93]. Ischemia and NMDARexcitotoxicity were used to induce neuronal death in thosecultures. The study showed that each of the three wild-type connexins induced functional (channel-permeable)GJs and supported neuronal death. The data suggestedthat the role of neuronal GJs in cell death is connexintype-independent and presumably relies on channelactivities of GJ complexes among neurons [93].Another model for the role of GJC in cell death postu-lates that connexins are not involved in cell death mech-anisms via their channel activities, but through direct orindirect regulation of transcriptional programs andapoptotic pathways [96, 104]. This model is based uponthe following observations (however, mostly obtained fornon-neuronal connexins). In osteocytes, Cx43 proteinserves as part of a trans-membrane signal transductionpathway that alters the activity of pro-apoptotic Bcl-2protein, Bad [105]. In non-neuronal cancer cells, Cx26and Cx43 are co-localized with Bcl-2 proteins (Bak, Bcl-xL and Bax) and participate in cell death pathways viadirect interaction with these pro-apoptotic factors[106, 107]. Overexpression of Cx43 in U251 glioblast-oma cells does not increase GJC, but is pro-apoptotic[108]. During ischemia in cardiomyocytes, Cx43 servesas part of a multiprotein complex in mitochondrialmembranes and controls homeostasis of mitochondria[109, 110]. Interference with expression of variousconnexins changes the expression of subsets of apop-totic factors (multiple studies reviewed in [96]) thatpresumably occurs through direct transcriptional con-trol via the “connexin response elements” in pro-apoptotic genes [111] or via direct interaction ofconnexins with transcriptional regulators (e.g., β-catenin) [112]. In addition, a connexin-dependent induc-tion of apoptosis can be connexin- and cell-specific asapoptosis in umbilical vein endothelial cells is induced byoverexpression of Cx37 (but not Cx40 or Cx43), however,overexpression of Cx37 in rat NRK kidney epithelial cellsis not pro-apoptotic [113]. A recent study in neuronal cul-tures utilized a lentiviral transduction of four mutant con-nexins (including various Cx36 and Cx43 mutants), eachof which induced dysfunctional (channel-impermeable)GJs [93]. None of those mutant connexins supportedneuronal death caused by ischemia or NMDAR excito-toxicity. This supported the notion that Cx36 unlikelyplays a role in neuronal death via channel-independentmechanisms, but likley plays a role via channel-dependent mechanisms. It remains to be exploredThe Author(s) BMC Cell Biology 2017, 18(Suppl 1):4 Page 5 of 11whether or not other neuronal connexins (e.g., Cx45)may contribute to neuronal death through the channel-independent mode of action.Finally, the role of connexin hemichannels in cell deathand survival has been proposed. Specifically, for the ner-vous system, the contribution of glial hemichannels viarelease of various channel-permeable “pro-death” agentshas been discussed [96, 103, 114, 115]. These agents pre-sumably include glutamate, ATP, reactive oxygen and ni-trogen species. The existence and role of neuronalhemichannels in neuronal death also has been suggestedbased on experiments with the use of various neuronalinjury models [11, 116]. However, other studies did notsupport the role of neuronal hemichannels in neuronaldeath following ischemia and NMDAR-mediated excito-toxicity [91, 93]. Moreover, the role of Cx36 hemichannelsin neuroprotection via release of ATP has been suggested[117], adding an additional layer of complexity on thecontribution of hemichannels in particular, and connexinsin general, to neuronal death and survival.Expression and regulation of astroglial connexinsIn the CNS, astrocytes are highly coupled to each otherby GJs and play a significant role in the metabolic andtrophic support of neurons [118]. These GJs are com-posed primarily of the channel protein Cx43, and to alesser extent Cx30 [119] and Cx26 [120]. GJs form afunctional syncytium of coupled astrocytes, contributingto spatial buffering, in dealing with elevated concentra-tions of extracellular potassium ions (K+) during in-creased neuronal activity; GJs assist in dispersal of K+accumulated by astrocytes [121].A major advance in understanding astrocytic GJs andconnexins was made through transgenic and knockoutmice (reviewed in [122]). The role of astrocytic GJs hasbeen demonstrated in mouse hippocampal slices, withCx43/Cx30 double knockout mice showing impairedextracellular K+ buffering compared to wild-type mouseslices [123]. It has also been shown that Cx43 plays arole in transient intracellular K+ buffering by mitochon-dria [124]. Pannasch et al. [10] reported key changes inastrocytic and neuronal properties in the absence ofCx43 and Cx30, revealing a major role for astrocyticnetworks in glutamate clearance, K+ buffering, andvolume regulation of the extracellular space during syn-aptic activity. Failure to efficiently clear K+ and glutam-ate results in prolonged neuronal AMPA and NMDAcurrents, as well as astroglial membrane depolarization.Further clarification of the role of Cx30 was obtained byexamining the hippocampus of single Cx30 knockoutmice, demonstrating that Cx30 modulates astrocyteglutamate transport, thereby controlling hippocampalexcitatory synaptic transmission [125]. In this case it wasshown that Cx30 controls astrocytic processes at thesynaptic cleft by modulating their morphology. Glutamateclearance by astrocytes was altered due to thesemorphological changes.In addition to forming GJs, Cx43 also forms hemi-channels, with single connexons communicating directlywith the extracellular space [126]. Hemichannelspredominantly exist in a closed state under normalphysiological conditions, due to ambient levels of Ca2+[127]. However, various cell stresses, such as hypoxia/reoxygenation and metabolic stress, have been reportedto cause opening of hemichannels in cultured astrocytes[128]. Hemichannels enhance neuronal injury underischemic and proinflammatory conditions [129, 130].Regulation of Cx43 in neural developmentDue to the high level of GJC observed during neurodeve-lopment, particularly in the cortex [131, 132], it is not sur-prising that connexins have been shown to be involved.While neurons predominantly express Cx36 postnatally inthe rat and mouse (see above), at prenatal stages neuralprogenitor cells (NPCs), including radial glia, are highlycoupled and express Cx43 and Cx26 [47, 133–136]. Differ-ent approaches to determine the role of these connexinshave been reported, including knockout of Cx43[133, 137, 138] and knockdown of Cx43 and Cx26[134]. While there are some variations in the pheno-types obtained, attributed in part to strain differences[138], the role of Cx43 appears to be due to adhesivefunctions [134], and the C-terminal region is criticalfor NPC migration [133, 136]. Cx26 knockdown wasalso shown to impede NPC migration in the developingrat cortex [134]. Cx26 has been demonstrated to be asubstrate for focal adhesion kinase (FAK), or to functionin stabilizing cell contacts, possibly through interactionswith ZO-1 [139]. The authors suggest that FAK could actas scaffold protein, a function also suggested for Cx43.Since Cx30 is not expressed until 15 days after birth in themouse [119] it is not considered in this context.The activity and regulation of Cx43 and GJC in neuronalinjury and cell deathThe level of GJC between astrocytes, as well as hemichan-nel activity [140], have been shown to be regulated by anumber of factors, including neurotransmitters and neu-romodulators [141–145], extracellular ion concentrations[146] and various pharmacological agents [147–150].Astrocytic GJC and Cx43 expression are altered in variousbrain pathologies, including ischemia [151], stroke [152,153], brain tumours [154], multiple sclerosis [155], brainabscess [156], Alzheimer’s disease [14, 157], and epilepsy[158, 159].In addition, microglial response to brain injury and dis-ease leads to the release of proinflammatory cytokines, in-cluding IL-1β and TNF-α, which impair astrocytic GJC,The Author(s) BMC Cell Biology 2017, 18(Suppl 1):4 Page 6 of 11but enhance hemichannel activity [160]; this leads toincreased neuronal injury. Short application of NMDA in-duces delayed neuronal injury due to excessive release ofglutamate after removal of NMDA [161]. However, neuronsin contact with astrocytes are protected against such glu-tamate toxicity [162, 163]. This neuronal protection was at-tributed to glutamate uptake by astrocytes [164], and as GJsare permeable to glutamate [165], GJC in astrocytes couldimprove glutamate uptake contributing to its dissipation,and thus to neuronal protection. In addition, GJC enablesthe intercellular trafficking of glucose and its metabolitesthrough the astroglial network from blood vessels to distalneurons in an activity-dependent manner [166]. This path-way could sustain neuronal survival in pathological situa-tions that alter energy production, such as hypoglycemia oranoxia/ischemia.Consideration of pannexinsA three-member family of cell membrane channels, thepannexin(s) (Panx 1, 2 and 3), should also be consideredin the context of GJ channels and hemichannels in theCNS. Panxs were discovered due to their homology tothe invertebrate GJ proteins, innexins [167, 168]. Panx1and Panx2 are present in the CNS [169] and have beenlinked to different CNS injury models [170–172]. Be-cause of the ubiquitous expression of Panx1 [168], it hasbeen the most widely investigated member of the Panxfamily [172, 173], however, a recent study reported thatPanx2 expression is not only limited to the CNS [174].Like the connexins, the Panxs traverse the cell mem-brane, but these large pore\channels allow the passage oflarge signaling molecules (e.g., ATP; glucose andglutamate) only between intra- and extracellular com-partments of neurons and possibly astrocytes [175–177],but not between adjoining cells. The evidence for Panxchannels not forming intercellular GJ channels, butrather the equivalent of a connexin hemichannel, hasbeen recently addressed [178] and is attributed to thesteric hindrance provided by the extracellularly glycosyl-ated arginine residue, which interferes with the couplingof two opposing Panx channels [179, 180]. Similarly toconnexins, the Panx C-terminal domain, particularlyfrom Panx1, has been shown to interact with a host ofintracellular factors under specific physiological andpathophysiological conditions [181–183].Because Panx1 forms channels in the plasma membrane,it likely participates in non-synaptic forms of communica-tion to regulate synaptic function under normal conditions,in addition to astrocytic Ca2+ wave propagation and regula-tion of vascular tone [184–186]. Unlike the protective ef-fects of Cx43, however, Panx1 activation under pathologicalconditions is detrimental, contributing to ischemia-inducedexcitotoxicity and ATP-dependent cell death [176, 187–191]. Under ischemic conditions, as seen with oxygen-glucose deprivation in cortical and hippocampal slices,Panx1 channels are irreversibly activated (opened) to pro-mote a progressive and uncontrollable depolarization ofneurons, sustained increments in extracellular concentra-tions of glutamate and aspartate, and subsequent activationof downstream apoptotic and necrotic pathways [192].Others have shown similar association between Panx1 ac-tivity and neuronal death, in different types of neurons[190, 193]. This suggests that Panx1-dependent cell deathmay be a common mechanism in injured neurons.In addition to the anoxic depolarization mechanismassociated with Panx1, it has also been implicated incontributing to inflammation [188, 194]. For example,cells undergoing apoptosis release chemotactic inflam-matory factors to promote phagocytic removal of deadcells. ATP and UTP represent important signaling mole-cules throughout the inflammatory cascade, also thoughtof as danger signals that are released from damaged andnecrotic cells, at least during the initial stages of ische-mia [195], but also more importantly through the Panxand connexin hemichannels. Several studies have re-ported that Panx1-mediated ATP and UTP release is in-duced by caspase activity (caspase 3 and 7) in apoptoticcells [176, 187, 189]. Two potential caspase cleavagesites were identified in the C-terminal of Panx1 [189].The C-terminal cleavage-site-B of Panx1 is evolutionarilyconserved among Panx1 homologues, indicating thatcaspase-dependent cleavage of Panx1 and ATP releasemay be a conserved mechanism in apoptosis [189].Caspase-mediated C-terminal cleavage of Panx1 results inirreversible channel opening, inducing higher if not un-controllable extracellular release of ATP. Findings fromseveral different organ systems collectively suggest thatthis irreversible activation of Panx1 leads to a cascade ofmaladaptive immunity, to include sustained cytokine re-lease, improper resolution of inflammation, impaired im-mune cell chemotaxis, and ultimately cell death [196].Panx1 activity has also been associated in triggering acti-vation of the inflammasome complex [188], however, thisassociation is not fully elucidated and maybe cell-type spe-cific [176, 188]. Of relevance here, in an in vivo experi-mental model of retinal ischemic injury in male mice,genetic ablation of Panx1 suppresses interleukin produc-tion and protects retinal neurons from injury, highlightingthe link between Panx1 and inflammation [193].Interestingly, the reported predominance of caspaseactivation after ischemic injury in female mice [197]raises the intriguing possibility that the endogenousrequirements for Panx1 to regulate neuronal responsesto ischemic injury are different between the two sexes.With respect to connexins, whether Panx membranechannels affect connexin activity, under physiological orpathological conditions, is unknown and potentially afruitful avenue for investigation.The Author(s) BMC Cell Biology 2017, 18(Suppl 1):4 Page 7 of 11Abbreviations5-HT2: Subfamily of serotonin receptors; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP: Adenosine triphosphate;CaMKII: Ca2+/calmodulin-dependent protein kinase II; cAMP: Cyclic adenosinemonophosphate; CNS: central nervous system; FAK: Focal adhesion kinase;GABA: γ-aminobutyric acid; GJ: Gap junction; GJC: Gap junction coupling;IP3: Inositol 1,4,5-trisphosphate; mGluR: Metabotropic glutamate receptor;NMDAR: N–methyl–D–aspartate receptor; NPC: Neural progenitor cell;Panx: Pannexin; PKA: Protein kinase A; PKC: Protein kinase C; UTP: UridinetriphosphateAcknowledgementsThis work was supported by NIH (R21 NS076925) and the University ofKansas Medical Center funds to A.B.B., in part by KUMC funds to J.D.F., andby a grant from the Canadian Institutes of Health to C.C.N. M.F.A. was fundedby a Heart & Stroke Foundation of Canada Fellowship. C.C.N. holds a CanadaResearch Chair in Gap Junctions and Neurological Disorders.DeclarationsThis article has been published as part of BMC Cell Biology Volume 18Supplement 1, 2017: Proceedings of the International Gap JunctionTherapeutic avenuesAs discussed above, multiple studies have indicated thatblockade of GJs and hemichannels provides neuroprotec-tion in various models of neuronal injury. This suggests apossibility for using the GJ/hemichannel blockade as anovel therapeutic approach. Conceptually, blocking thepropagation between the neurons of GJ-permeable toxicsignals or blocking the release of toxic agents via hemichan-nels would create a “firebreak”, reducing the extent of celldeath. This would prevent excessive neuronal death follow-ing ischemic stroke, TBI and epilepsy, significantly reducingmorbidity and mortality. Because clinical trials for NMDARantagonists as neuroprotective agents largely failed [198],development of new neuroprotective agents based on ma-nipulation of neuronal and astroglial GJs and hemichannelsshould prove to be a valuable alternative approach.ConclusionHowever, as also discussed in the present review, a numberof reports suggest that blockade of GJs and hemichannelsincreases cell death. Clearly, the data on whether GJs arepro-death or pro-survival are conflicting and a convincing,evidence-supported explanation of this phenomenon isabsent. This provides the significant barrier for translatingthe above-described findings to clinical practice. Withoutresolution of conflicting studies, manipulation of GJC inthe clinic, as a novel approach to reduce neuronal death,cannot be advocated. This represents loss of a potentiallyextraordinary benefit to people suffering a range of braininsults. Identifying the underlying mechanisms and deter-mining conditions for the clinical use of GJ blockers thatwill not compromise their strong neuroprotective effectsshould be the major focus of future studies.Conference 2015: second issue. The full contents of the supplement areavailable online at http://bmccellbiol.biomedcentral.com/articles/supplements/volume-18-supplement-1.FundingFunding for publication of this article was obtained from University of KansasMedical Center (KUMC to JDF).Authors’ contributionsAll authors read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Ethics approval and consent to participateThere are no requirements for ethics and consent.Author details1Department of Molecular & Integrative Physiology, University of KansasMedical Center, The University of Kansas, Kansas City, KS 66160, USA.2Department of Biochemistry and Molecular Biology, University of KansasMedical Center, The University of Kansas, Kansas City, KS 66160, USA.3Department of Cellular & Physiological Sciences, Faculty of Medicine, LifeSciences Institute, The University of British Columbia, 2350 Health SciencesMall, Vancouver, BC V6T 1Z3, Canada.Published: 17 January 2017References1. 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