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Immunology and Microbiology » "Natural Remedies in the Fight Against Parasites", book edited by Hanem Khater, M. Govindarajan and Giovanni Benelli, ISBN 978-953-51-3290-5, Print ISBN 978-953-51-3289-9, Published: July 12, 2017 under CC BY 3.0 license. © The Author(s).

Chapter 6

Involvement of Gap Junction Proteins in Infectious Diseases Caused by Parasites

By José Luis Vega, Iván Barría, Juan Güiza, Jorge González and Juan C. Sáez
DOI: 10.5772/67187

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Model of the possible participation of gap junction proteins in the invasion of host cells by Trypanosoma cruzi. Parasites release a virulence factor, which opens Pannexin 1 channels allowing the release of ATP to the extracellular milieu. The ATP activates P2Y1 receptors and promotes Ca2+ release from intracellular stores generating intracellular Ca2+ transients, which induces the opening of new hemichannels formed by connexin or pannexins. These effects promote the Trypanosoma cruzi invasion.
Figure 1. Model of the possible participation of gap junction proteins in the invasion of host cells by Trypanosoma cruzi. Parasites release a virulence factor, which opens Pannexin 1 channels allowing the release of ATP to the extracellular milieu. The ATP activates P2Y1 receptors and promotes Ca2+ release from intracellular stores generating intracellular Ca2+ transients, which induces the opening of new hemichannels formed by connexin or pannexins. These effects promote the Trypanosoma cruzi invasion.

Involvement of Gap Junction Proteins in Infectious Diseases Caused by Parasites

José Luis Vega1, Iván Barría1, Juan Güiza1, Jorge González2 and Juan C. Sáez3, 4
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Parasitic diseases affect low-income nations with health consequences that affect the economy of these countries. Research aimed at understanding their biology and identification of potential targets for drug development is of the highest priority. Inhibitors of channels formed by proteins of the gap junction family such as suramin and probenecid are currently used for treatment of parasitic diseases caused by pathogenic protozoan. Gap junction proteins are present in both vertebrates and invertebrates permitting direct and indirect cellular communication. These cellular specializations are formed by two protein families corresponding to connexins (vertebrates) and innexins (invertebrates). In addition, a third protein family composed by proteins denominated pannexins is present in vertebrates and shows primary sequence homology to innexins. Channels formed by these proteins are essential in many biological processes. Recent evidences suggest that gap junction proteins play a critical role in bacterial and viral infections. Nonetheless, little is known about the role of these channels in parasitic infections. In this chapter, we summarized the current knowledge about the role of gap junction family proteins and channels in parasitic infections.

Keywords: connexins, pannexins, innexins, cellular communication, parasites

1. Introduction

The gap junction protein families include connexin, pannexin, and innexin proteins [1]. Connexin and innexin proteins form gap junction channels, which connect the cytoplasm of neighbouring cells, or connexin, pannexin and innexin proteins form channels (a half of gap junction channel) that connect the intra- and extracellular milieu [1]. In humans, connexins and pannexins are encoded by 21 and 3 genes, respectively [1]. Moreover, it has been identified 25 and 8 innexin genes in Caenorhabditis elegans and Drosophila melanogaster, respectively [2, 3]. It is known that Panx1 channels participate in response to bacterial and viral infections; however, little is known about the role of Panx1 channels and gap junction channels in infections caused by parasites [47] (Table 1). For example, Shigella flexneri, which is a causative agent of bacillary dysentery, causes opening of hemichannels formed by connexin 26 [4], which favours its spread and invasion [4]. Also, blockade of Panx1 channels has been shown to inhibit HIV replication in CD4(+) T lymphocytes [6]. In this chapter, we summarized the current knowledge about how the parasite infections modulate channels formed by gap junction proteins in host cells and the cellular pathways involved in this phenomenon. We also comment on channel blockers currently used in medicine for treatment of parasitic diseases caused by pathogenic protozoan (Table 2).

Gap junction proteinsParasiteCell typeEffectsReferences
Cx43Trypanosoma cruziCardiomyocytesDownregulated[43]
Leptomeningeal cellsDownregulated[44]
Cardiomyocytes and heart human biopsiesDownregulated[50]
Toxoplasma gondiiAstrocytesDownregulated[44]
Leptomeningeal cellsDownregulated[44]
Cx26Toxoplasma gondiiAstrocytesDownregulated[44]
Cx37Trypanosoma cruziHeart from chagasic mouseUpregulated[52]
Cx40Trypanosoma cruziHeart from chagasic mouseNot change[52]
Cx45Trypanosoma cruziHeart from chagasic mouseNot change[52]
Trypanosoma cruziCardiomyocytesUpregulated[51]
Panx1Plasmodium falciparumHuman erythrocytesIncreased ATP release[54]
Entamoeba histolyticaHuman monocytic cellsIncreased ATP release[60]
AGAP001476Plasmodium falciparumMidgut tissues from Anopheles gambiaeUpregulated[61]
Plasmodium bergheiMidgut tissues from Anopheles gambiaeUpregulated[61]

Table 1.

Summary of published works on the effect of parasite infections on the gap junction proteins.

DrugCommercial namePresentation and quantityCompanyCountry production
ProbenecidProbalanTablets 500 mgLannettUSA
ProbenecidProbenecid & ColchicineTablets 500 mgWatsonINDIA
ProbenecidProbenecidTablets 500 mgMylanUSA
ProbenecidProbenecid & ColchicineTablets 500 mgIngenusUSA
SuraminGermaninVial 1 gBayerGermany

Table 2.

Commercial drugs.

2. The family of gap junction proteins

Gap junction proteins are present in both vertebrates and invertebrates from mesozoa to mammals [8]. In chordate animals, gap junction channels are encoded by a family of genes called connexins (Cxs) [9] (Table 3). In addition, gap junction communication of invertebrate is mediated via another family of proteins called innexins (Inxs) [8]. Inx homologues have been identified in vertebrates and were termed pannexins (Panxs) [10]. Members of the same protein family oligomerize in hexamers forming channels, which are inserted into the plasma membrane connecting the intra- and extracellular milieu [8]. Whereas, docking of two channels forms intercellular channels (gap junction channels) that connect the cytoplasm of two cells [8]. It has been proposed that Panx-based channels do not form gap junction channels due to their post-translational glycosylation [11]. However, this theoretical prediction might be proved wrong because in exogenous cells systems forms functional gap junctions. In support to this possibility is the fact that Panx1 expressed in exogenous cell systems forms functional gap junctions [12, 13].

ATPAdenosine triphosphate
cAMPCyclic adenosine monophosphate
CDSCoding region sequence
DCSFDivalent cation solution free
P.FalciparumPlasmodium falciparum
PMAPhorbol 12-myristate 13-acetate
T. cruziTrypanosoma cruzi
UTRUntranslated region

Table 3.


2.1. Genes

The first Cx gene was cloned in 1986, and there are at least 21 Cx isoforms in the human genome [8, 14]. Most Cx genes have a first exon containing only 5′-untranslated region (UTR) sequences and a large second exon containing the complete coding region sequence (CDS) as well as all remaining untranslated sequences [8]. Exceptions to this gene structure are the Cx32, Cx36, and Cx45 genes [8]. Panx are termed as Panx1, Panx2, and Panx3 and are present both in invertebrate and chordate genomes [15, 16]. The human and mouse genome contain three Panx-encoding genes [10]. The genomic sequence revealed that human Panx1 contains five exons with four introns [10]. Moreover, Panx2 and Panx3 contain four exons [10]. The first Inx gene was identified in 1998 as a result of genome sequencing of nematode C. elegans [17]. Actually, 25 and 8 Inx genes in C. elegans and D. melanogaster have been identified, respectively [2, 3]. Usually, Inx genes are encoded on multiple exons and have the potential to produce more than one protein by differential splicing [18]. Recently, viral homologs of Panxs/Inxs were identified in Polydnaviruses and denominated vinnexins (Vinx) [19].

2.2. Secondary structure

Cx, Inx, and Panx proteins share the same membrane topology, characterized by four transmembrane domains connected by two extracellular loops and a single cytoplasmic loop [20]. These extracellular loops contain 2 (for Panxs and Inxs) or 3 (for Cxs) highly conserved cysteine residues [21]. Moreover, the intracellular loop is highly variable [21]. The four transmembrane domains are well-conserved among members of the same family of proteins and form alpha-helical sheets that contribute to the wall of the HC and line its central hydrophilic space [21]. All members of the 3 families have their NH2- and COOH-terminal region within the cytoplasm [21]. The COOH-terminal region differs in length and sequence in all gap junction proteins [21]. Inx proteins have a highly conserved pentapeptide YYQWV close to, or at, the beginning of the second transmembrane domain [22].

2.3. Gap junctional channels

Gap junctions are specialized cell-to-cell junctions that mediate direct intercellular communication between cells [8]. Depending on whether the two interacting channels are made of the same or different Cxs, gap junction plaques are formed by homo- and heterotypic channels, respectively, with distinct biophysical characteristics [21]. These intercellular channels are essential in several Physiologic tissue functions such as electrical conduction between cardiomyocytes [23], development and regeneration of skeletal muscle [24], endocrine gland secretion [25], and ovarian folliculogenesis [26]. They are also implicated in pathophysiological conditions including hereditary deafness [27], cataract [28], ectodermal dysplasias [29], tumorigenesis [30], and neuroinflammatory responses [31].

2.4. Hemichannels (HCs)

Several studies have shown that HCs allow the bidirectional passage of ions and cytosolic signaling molecules, such adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+), glutamate, glutathione, and prostaglandins [32]. Under physiological conditions, HCs are involved in the regulation of cell volume [33], vascular tone [34], hemostasis [35], and neuroglia paracrine interactions [36], among others. However, HCs have been the focus of interest because of their relevance in pathological conditions, including metabolic inhibition [37], stroke [38], myocardial infarction [39, 40], ischemic neuronal death [41], spinal cord injury [42], diarrhoea during infectious enteric disease [5], and keratitis-ichthyosis-deafness syndrome [43].

The presence and functional HCs in the plasma membrane have been determined through several techniques such as electrophysiology, uptake of fluorescent dyes, and release of adenosine triphosphate (ATP) [44]. Due to the existence of non-selective channels in the plasma membrane, there are significant considerations for studying HCs [45]. These criteria are as follows: (i) cell expression of at least one Cx/Panx isoform at the plasma membrane, (ii) the ability of the cells to incorporate or release molecules, (iii) to mediate membrane currents with conductance associated to Cx/Panx HCs, (iv) the abolishment of HC function using a pharmacologic approach (e.g. La3+, probenecid, or carbenoxolone) or mimetic peptide blockers (Gap19, Gap26, Gap27 for specific Cx HCs or 10Panx1 for Panx1 HCs), and (v) to demonstrate that blockade of HCs affect physiological responses [44, 45].

3. Gap junction proteins in parasitic infections

3.1. Connexins (Cxs)

3.1.1. Functional studies

Pioneering studies in the 1990s by de Carvalho et al., 1992 showed that Trypanosoma cruzi induces a gap junction alteration in cardiac myocytes [46] (Table 1). They showed that T. cruzi infection reduces the junctional conductance and Lucifer yellow transfer in cardiomyocytes, revealing that this parasite infection reduces the channel function of host cells [46]. The same researchers also showed that infection caused by Toxoplasma gondii reduces intercellular communication in astrocytes and leptomeningeal cells [47]. Recently, we demonstrated that T. cruzi increases dye uptake via HCs in non-confluent Cx43-HeLa cells [7]. Suramin, an anti-protozoa drug, inhibits the activity of HCs [48]. Suramin causes a concentration-dependent inhibition of a divalent cation-free solution (DCSF)-induced dye uptake in a rat kidney epithelial cell line [48]. Also, suramin blocks the DCSF-induced ATP release in a rat kidney epithelial cell line [48]. Interestingly, the suppressive effect of suramin on the influx of dye and efflux of ATP was not reproduced by PPADS, a broad-spectrum antagonist of P2 receptors, suggesting that the action of suramin on HCs is independent of its action on P2 purine receptors [48]. Also, suramin (300 μM for 12 h) did not affect the total Cx43 level [48]. Moreover, prolonged incubation of T. cruzi-infected LLC-MK2 cells in the presence of suramin (500 µM) causes morphological changes on trypomastigote forms characterized by an accentuated decrease on parasite motility [49]. In trypomastigotes, suramin causes a decrease in ~5% in cell length and an increase in ~43% in cell width [49]. Also, it was observed that 95% of trypomastigotes exposed to suramin present a partial or even total detachment of the flagellum from the cell body [49].

3.1.2. Protein expression alterations

At the protein level, T. cruzi reduces Cx43 levels at junctional membrane regions in neonatal rat cardiomyocytes [46, 47]. Other studies in mouse cardiomyocytes showed that T. cruzi reduces Cx43 levels at 24-h post-infections [50]. Interestingly, cardiomyocytes with pronounced decrease in Cx43 protein levels showed an increased number of intracellular amastigotes, suggesting a direct relationship between host cell parasitism and Cx43 downregulation in vitro [50]. Also, it has been described that infection with T. cruzi or T. gondii reduces the levels of Cx43 and Cx26 protein in astrocytes or leptomeningeal cells [47]. In vivo model of T. cruzi infection showed a significant reduction in myocardial Cx43 protein levels [50]. Swiss Webster mice infected with T. cruzi showed a reduction in Cx43 levels in atrium and ventricles at 11- or 30-day post-infection, respectively [50]. Moreover, brain slices prepared from mice infected with T. gondii showed complete absence of Cx43 immunoreactivity within the cysts and marked reduction in the surroundin tissue [47]. The same study described a reduction of Cx43 protein levels in whole brains of T. cruzi-infected mice [47]. In monkeys, T. cruzi infection causes significant Cx43 loss in the cardiac tissue [51]. Clinical studies described that samples from chagasic patients showed alterations of cardiac Cx levels [52]. Immunohistochemical analysis of left ventricle biopsies from subjects with chronic chagasic disease showed reduction in both mean number (<20%) and size (<2.2 fold) of Cx43 plaques [52].

3.1.3. Gene expression regulation

Gene profiling of T. cruzi-infected cardiomyocytes revealed downregulation at 48 h after infection of GJA1 and GJC1 genes, which encode for Cx43 and Cx45, respectively [53]. Upregulation of GJA4 gene encoding Cx37, a major endothelial cell Cx, was also described [54].

3.1.4. Cx knock-out mice and parasitic infections

Hepatic granulomas induced by Schistosoma mansoni infection in Cx43 deficient mice showed a higher degree of fibrosis and a reduced index of cell proliferation at 8 and 12 weeks after infection [55]. However, no differences in the average area of granulomas or number of cells per granuloma were observed [55]. The authors of the above mention work suggested that deletion of one allele of Cx43 gene could be the cause of reduced gap junction channels that modifies the interactions between granuloma cells, thereby modifying the characteristics of granuloma [55].

3.2. Pannexins (Panxs)

It has been demonstrated that Plasmodium falciparum infection induces ATP release via Panx1 channels in human erythrocytes [56]. A mixture of isoproterenol (β-adrenergic agonist), forskolin (adenylate kinase activator), and papaverine (phosphodiesterase inhibitor) induce cyclic adenosine monophosphate (cAMP)-dependent ATP release in human erythrocytes, and this effect was 3.8-fold higher in trophozoite-infected erythrocytes compared to uninfected erythrocytes [56]. Interestingly, this effect was reduced by 100 µM carbenoxolone or 100 nM mefloquine, two Panx1 channel blockers [54]. These authors suggest that the increased ATP release from infected red cells could be mediated by by Panx1 channels [56]. Several studies have shown that probenecid has a marked antimalarial effect [5759]. The incubation of P. falciparum with probenecid shows antimalarial activity at concentrations >150 μM at day 2 of treatment [57]. However, probenecid at concentration <150 μM increases the P. falciparum sensitivity to antifolate drugs [57]. For example, in the presence of 50 µM probenecid, the IC50 (nM) was reduced from 1.42 ± 0.52 to 0.52 ± 0.36, from 215 ± 150 to 36.50 ± 26.80 and from 33.53 ± 12.30 to 1.77 ± 2.70 for pyrimethamine, sulfadoxine, and dapsone, respectively [57]. Probenecid also reverses the chloroquine resistance of P. falciparum and increases piperaquine activity in vitro [57]. Also, probenecid chemosensitize a multidrug-resistant strain V1S of P. falciparum to piperaquine [59]. Moreover, antimalarial drugs such as artemisinin and artesunate also inhibit Panx1 channel [60]. For example, artesunate causes a concentration-dependent inhibition of membrane current mediated by Panx1 channels with an IC50 of 450 µM, while 200 µM artemisinin causes a membrane current reduction of about 20% in Xenopus oocytes [60]. Moreover, artemisinin also inhibits dye uptake with an IC50 of 0.14 µM in frog erythrocytes [60]. Moreover, 100 nM mefloquine significantly reduces voltage-activated Panx1 channel currents in astrocytes from Cx43-null mice [61]. Also, mefloquine blocks dye uptake induced by ATP in astrocytes from Cx43-null mice [61]. In addition, it has been described that Entamoeba histolytica induces ATP release into the extracellular space through opening of Panx1 channels in macrophages [62]. Incubation with 500 µM 10Panx1, a mimetic blocking peptide of Panx1 channels, abolished ATP release in response to E. histolytica in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 human monocytic cells [62]. The same results were observed with 100 μM carbenoxolone or 250 μM probenecid [62].

3.3. Innexins (Inxs)

It has been demonstrated that Inx proteins have a critical role for mediating anti-Plasmodium responses in Anopheles gambiae [63]. It has been shown that AGAP001476 mRNA levels were induced during Plasmodium infection in Anopheles midguts [63]. The carbenoxolone-treated mosquitoes showed an increase in both Plasmodium oocyst number and infection rate [63].

4. Possible role of gap junction proteins in parasite infections

Although the role of gap junction proteins in parasitic infections has not been fully elucidated, they could participate in responses that include changes in plasma membrane permeability, signalling, and inflammasome activation.

4.1. Alteration of the host cell membrane permeability

A common condition and often necessary for infection is the alteration of the host cell membrane permeability [64, 65], and hemichannel activity can considerably affect the permeability of the cell membrane in mammalian cells [66]. For example, T. cruzi alters the plasma membrane permeability in host cells during different stages of the disease [65, 6769]. Another parasite that alters the plasma membrane permeability is P. falciparum. This parasite invades and replicates asexually within human erythrocytes and enhances plasma membrane permeability in different stages of the disease [70, 71]. The apicomplexan Babesia divergens also increases the membrane permeability of erythrocyte [64]. The mechanism for such erythrocyte permeabilization is different in transport rates, solutes selectivity, and temperature dependence compared with the alteration induced by P. falciparum [64].

4.2. Intracellular Ca2+ mobilization

Gap junction proteins participate in Ca2+ signalling, and they constitute one pathway for intercellular Ca2+ wave propagation in cardiomyocytes, astrocytes, and osteocytes, among other cell types [72]. In addition, Cx26, Cx32 and Cx43 HCs are permeable to Ca2+ [7376] and might be involved in initiation of intracellular rise in Ca2+ signals. In protozoan infections, a key process in early stages of invasion is the rise in cytosolic Ca2+ concentration [77]. For example, when T. cruzi comes into contact with the host cell, triggers a transient increase in cytosolic Ca2+ concentration that induces lysosome exocytosis in host cells [65, 77]. This process is required for cell invasion, because chelating the intracellular Ca2+ transients in host cells reduces the entry of the parasite into the cell [78]. Figure 1 shows a model of the possible participation of pannexin channel in intracellular Ca2+ mobilization during the invasion by T. cruzi.


Figure 1.

Model of the possible participation of gap junction proteins in the invasion of host cells by Trypanosoma cruzi. Parasites release a virulence factor, which opens Pannexin 1 channels allowing the release of ATP to the extracellular milieu. The ATP activates P2Y1 receptors and promotes Ca2+ release from intracellular stores generating intracellular Ca2+ transients, which induces the opening of new hemichannels formed by connexin or pannexins. These effects promote the Trypanosoma cruzi invasion.

4.3. Activation of the inflammasome

The inflammasome activation triggers innate immune defence by inducing the processing of pro inflammatory cytokines, such as IL-1, in a caspase 1-dependent manner [79]. Panx1 channels play a key role in inflammasome activation [79]. It has been proposed that small pathogen-associated molecule patterns (PAMPs) can gain cytosolic access via the P2X7 receptor/Panx1 (P2X7R/Panx1) complex and activate the inflammasome [79].

5. Conclusions

Parasitic infections affect predominantly underprivileged areas of the world and represent serious life-threatening conditions in high-risk groups such as young children, elderly, and immune deficient subjects. Also, therapeutic options include a wide variety of compounds with considerable toxic and undesirable side effects. The introduction of knockout animals and specific inhibitors has increased our understanding about the role of Cx, Panx, and Inx proteins in the pathophysiology of many infectious conditions. However, their participation in infections caused by parasites is not completely elucidated. A variety of methods have been used to evaluate changes in gap junction protein expression during parasite infections. These methods include Western blot, immunofluorescence, or functional studies such dye uptake, dye coupling, or current measurements with electrophysiological techniques. In summary, the available data suggest that the parasite infections modulate gap junction proteins in host cells. In this context, characterization of gap junction proteins and their functions in protozoan parasites might facilitate the design of effective new therapies to fight protozoan infections such as malaria and Chagas disease.


This work was partially supported by FONDECYT grants 11130013 (to JLV) and 1131007 (to JG) and ICM-Economía grant P09-022-F (to JCS).


1 - Sáez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC. Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev. 2003;83:1359-1400. doi:10.1152/physrev.00007.2003
2 - Starich T, Sheehan M, Jadrich J, Shaw J. Innexins in C. elegans. Cell Commun Adhes. 2001;8:311-314. doi:10.3109/15419060109080744
3 - Stebbings LA, Todman MG, Phillips R, Greer CE, Tam J, Phelan P, Jacobs K, Bacon JP, Davies JA. Gap junctions in Drosophila: developmental expression of the entire innexin gene family. Mech Dev. 2002;13:197-205. doi:10.1016/S0925-4773(02)00025-4
4 - Tran Van Nhieu G, Clair C, Bruzzone R, Mesnil M, Sansonetti P, Combettes L. Connexin-dependent inter-cellular communication increases invasion and dissemination of Shigella in epithelial cells. Nat Cell Biol. 2003;8:720-6. doi:10.1038/ncb1021
5 - Guttman JA, Lin AE-J, Li Y, Bechberger J, Naus CC, Vogl AW, Finlay BB. Gap junction hemichannels contribute to the generation of diarrhoea during infectious enteric disease. Gut. 2010;59:218-226. doi:10.1136/gut.2008.170464
6 - Orellana JA, Velasquez S, Williams DW, Sáez JC, Berman JW, Eugenin EA. Pannexin1 hemichannels are critical for HIV infection of human primary CD4+ T lymphocytes. J Leukoc Biol. 2013;94:399-407. doi:10.1189/jlb.0512249
7 - Vega JL, Subiabre M, Figueroa F, Schalper KA, Osorio L, González J, Sáez JC. Role of gap junctions and hemichannels in parasitic infections. Biomed Res Int. 2013;2013:589130. doi:10.1155/2013/589130
8 - Meşe G, Richard G, White TW. Gap junctions: basic structure and function. J Invest Dermatol. 2007;127:2516-2524. doi:10.1038/sj.jid.5700770
9 - Goodenough DA. Bulk isolation of mouse hepatocyte gap junctions. Characterization of the principal protein, connexin. J Cell Biol. 1974;61:557-563. doi:10.1083/jcb.61.2.557
10 - Panchin YV. Evolution of gap junction proteins—the pannexin alternative. J Exp Biol. 2005;208:1415-1419. doi:10.1242/jeb.01547
11 - Sosinsky GE, Boassa D, Dermietzel R, Duffy HS, Laird DW, MacVicar B, Naus CC, Penuela S, Scemes E, Spray DC, Thompson RJ, Zhao HB, Dahl G. Pannexin channels are not gap junction hemichannels. Channels (Austin). 2011;5:193-197. doi:10.4161/chan.5.3.15765
12 - Bruzzone R, Hormuzdi SG, Barbe MT, Herb A, Monyer H. Pannexins, a family of gap junction proteins expressed in brain. Proc Natl Acad Sci U S A. 2003;100:13644-13649. doi:10.1073/pnas.2233464100
13 - Lai CP, Bechberger JF, Thompson RJ, MacVicar BA, Bruzzone R, Naus CC. Tumor-suppressive effects of pannexin 1 in C6 glioma cells. Cancer Res. 2007;67:1545-1554. doi:10.1158/0008-5472.CAN-06-1396
14 - Paul DL. Molecular cloning of cDNA for rat liver gap junction protein. J Cell Biol. 1986;103:123-134. doi:10.1083/jcb.103.1.123
15 - Phelan P, Bacon JP, Davies JA, Stebbings LA, Todman MG, Avery L, Baines RA, Barnes TM, Ford C, Hekimi S, Lee R, Shaw JE, Starich TA, Curtin KD, Sun YA, Wyman RJ. Innexins: a family of invertebrate gap-junction proteins. Trends Genet. 1998;14:348-349. doi:10.1016/S0168-9525(98)01547-9
16 - Baranova A, Ivanov D, Petrash N, Pestova A, Skoblov M, Kelmanson I, Shagin D, Nazarenko S, Geraymovych E, Litvin O, Tiunova A, Born TL, Usman N, Staroverov D, Lukyanov S, Panchin Y. The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics. 2004;83:706-716. doi:10.1016/j.ygeno.2003.09.025
17 - C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science. 1998 Dec 11;282(5396):2012-8. doi:10.1126/science.282.5396.2012
18 - Crompton D, Todman M, Wilkin M, Ji S, Davies J. Essential and neural transcripts from the Drosophila shaking-B locus are differentially expressed in the embryonic mesoderm and pupal nervous system. Dev Biol. 1995;170:142-158. doi:10.1006/dbio.1995.1203
19 - Kroemer JA, Webb BA. Polydnavirus genes and genomes: emerging gene families and new insights into polydnavirus replication. Annu Rev Entomol. 2004;49:431-56. doi:10.1146/annurev.ento.49.072103.120132
20 - Barbe MT, Monyer H, Bruzzone R. Cell-cell communication beyond connexins: the pannexin channels. Physiology (Bethesda). 2006 Apr;21:103-14. doi:10.1152/physiol.00048.2005
21 - Bosco D, Haefliger JA, Meda P. Connexins: key mediators of endocrine function. Physiol Rev. 2011 Oct;91(4):1393-445. doi:10.1152/physrev.00027.2010
22 - Phelan P. Innexins: members of an evolutionarily conserved family of gap-junction proteins. Biochim Biophys Acta. 2005;1711:225-245. doi:10.1016/j.bbamem.2004.10.004
23 - Kanno S, Saffitz JE. The role of myocardial gap junctions in electrical conduction and arrhythmogenesis. Cardiovasc Pathol. 2001;10:169-177. doi:10.1016/S1054-8807(01)00078-3
24 - Araya R, Eckardt D, Maxeiner S, Krüger O, Theis M, Willecke K, Sáez JC. Expression of connexins during differentiation and regeneration of skeletal muscle: functional relevance of connexin43. J Cell Sci. 2005:118:27-37. doi:10.1242/jcs.01553
25 - Murray SA, Davis K, Gay V. ACTH and adrenocortical gap junctions. Microsc Res Tech. 2003;61:240-246. doi:10.1002/jemt.10332
26 - Gershon E, Plaks V, Dekel N. Gap junctions in the ovary: expression, localization and function. Mol Cell Endocrinol. 2008;282:18-25. doi:10.1016/j.mce.2007.11.001
27 - Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997;387:80-83. doi:10.1038/387080a0
28 - Xia CH, Chang B, Derosa AM, Cheng C, White TW, Gong X. Cataracts and microphthalmia caused by a Gja8 mutation in extracellular loop 2. PLoS One. 2012;7:e52894. doi:10.1371/journal.pone.0052894
29 - Scott CA, Tattersall D, O’Toole EA, and Kelsell DP. Connexins in epidermal homeostasis and skin disease. Biochimica et Biophysica Acta. 2012;1818:1952-1961. doi:10.1016/j.bbamem.2011.09.004
30 - Naus CC, Laird DW. Implications and challenges of connexin connections to cancer. Nat Rev Cancer. 2010;10:435-441. doi:10.1038/nrc2841
31 - Bennett MVL. Garré JM, Orellana JA, Bukauskas FF, Nedergaard M, Sáez JC. Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Res. 2012;1487:3-15. doi:10.1016/j.brainres.2012.08.042
32 - Kar R, Batra N, Riquelme MA, Jiang JX. Biological role of connexin intercellular channels and hemichannels. Arch Biochem Biophys. 2012;524:2-15. doi:10.1016/
33 - Quist AP, Rhee SK, Lin H, Lal R. Physiological role of gap-junctional hemichannels. Extracellular calcium-dependent isosmotic volume regulation. J Cell Biol. 2000;148:1063-1074. doi:10.1083/jcb.148.5.1063
34 - Billaud M, Sandilos JK, Isakson BE. Pannexin 1 in the regulation of vascular tone. Trends Cardiovasc Med. 2012;22:68-72. doi:10.1016/j.tcm.2012.06.014
35 - Vaiyapuri S, Jones CI, Sasikumar P, Moraes LA, Munger SJ, Wright JR, Ali MS, Sage T, Kaiser WJ, Tucker KL, Stain CJ, Bye AP, Jones S, Oviedo-Orta E, Simon AM, Mahaut-Smith MP, Gibbins JM. Gap junctions and connexin hemichannels underpin hemostasis and thrombosis. Circulation. 2012;125:2479-2491.
36 - Orellana JA, Froger N, Ezan P, Jiang JX, Bennett MVL, Naus CC, Giaume C, Sáez JC. ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels. J Neurochem. 2011;118:826-840. doi:10.1111/j.1471-4159.2011.07210.x
37 - Contreras JE, Sánchez HA, Eugenin EA, Speidel D, Theis M, Willecke K, Bukauskas FF, Bennett MVL, Sáez JC. Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc Natl Acad Sci U.S.A. 2002;99:495-500. doi:10.1073/pnas.012589799
38 - Thompson RJ, Zhou N, MacVicar BA. Ischemia opens neuronal gap junction hemichannels. Science. 2006;312:924-927. doi:10.1126/science.1126241
39 - Hawat G, Benderdour M, Rousseau G, Baroudi G. Connexin 43 mimetic peptide Gap26 confers protection to intact heart against myocardial ischemia injury. Pflugers Arch. 2010;460:583-592.
40 - Wang N, De Bock M, Antoons G, Gadicherla AK, Bol M, Decrock E, Evans WH, Sipido KR, Bukauskas FF, Leybaert L. Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation. Basic Res Cardiol. 2012;107:304. doi:10.1007/s00395-012-0304-2
41 - Orellana JA, Figueroa XF, Sánchez HA, Contreras-Duarte S, Velarde V, Sáez JC. Hemichannels in the neurovascular unit and white matter under normal and inflamed conditions. CNS Neurol Disord Drug Targets. 2011;10:404-414. doi:10.2174/187152711794653869
42 - Chen MJ, Kress B, Han X, Moll K, Peng W, Ji R-R, Nedergaard M. Astrocytic CX43 hemichannels and gap junctions play a crucial role in development of chronic neuropathic pain following spinal cord injury. Glia. 2012;60:1660-1670. doi:10.1002/glia.22384
43 - Levit NA, Mese G, Basaly MGR, White TW. Pathological hemichannels associated with human Cx26 mutations causing Keratitis-Ichthyosis-Deafness syndrome. Biochim Biophys Acta. 2012;1818: 2014-2019. doi:10.1016/j.bbamem.2011.09.003
44 - Retamal MA, Reyes EP, García IE, Pinto B, Martínez AD, González C. Diseases associated with leaky hemichannels. Front Cell Neurosci. 2015;9:267. doi:10.3389/fncel.2015.00267
45 - Sáez JC, Leybaert L. Hunting for connexin hemichannels. FEBS Lett. 2014;588:1205-1211. doi:10.1016/j.febslet.2014.03.004
46 - de Carvalho AC, Tanowitz HB, Wittner M, Dermietzel R, Roy C, Hertzberg EL, Spray DC. Gap junction distribution is altered between cardiac myocytes infected with Trypanosoma cruzi. Circ Res. 1992;70:733-742. doi:10.1161/01.RES.70.4.733
47 - Campos de Carvalho AC, Roy C, Hertzberg EL, Tanowitz HB, Kessler JA, Weiss LM, Wittner M, Dermietzel R, Gao Y, Spray DC. Gap junction disappearance in astrocytes and leptomeningeal cells as a consequence of protozoan infection. Brain Res. 1998;790:304-314. doi:10.1016/S0006-8993(97)01523-0
48 - Chi Y, Gao K, Zhang H, Takeda M, Yao J. Suppression of cell membrane permeability by suramin: involvement of its inhibitory actions on connexin 43 hemichannels. Br J Pharmacol. 2014;171:3448-3462. doi:10.1111/bph.12693
49 - Bisaggio DF, Campanati L, Pinto RC, Souto-Padrón T. Effect of suramin on trypomastigote forms of Trypanosoma cruzi: changes on cell motility and on the ultrastructure of the flagellum-cell body attachment region. Acta Trop. 2006;98:162-175. doi:10.1016/j.actatropica.2006.04.003
50 - Adesse D, Garzoni LR, Huang H, Tanowitz HB, de Nazareth Meirelles M, Spray DC. Trypanosoma cruzi induces changes in cardiac connexin43 expression. Microbes Infect. 2008;10:21-28. doi:10.1016/j.micinf.2007.09.017
51 - Carvalho CM, Silverio JC, da Silva AA, Pereira IR, Coelho JM, Britto CC, Moreira OC, Marchevsky RS, Xavier SS, Gazzinelli RT, da Glória Bonecini-Almeida M, Lannes-Vieira J. Inducible nitric oxide synthase in heart tissue and nitric oxide in serum of Trypanosoma cruzi-infected rhesus monkeys: association with heart injury. PLoS Negl Trop Dis. 2012;6:e1644. doi:10.1371/journal.pntd.0001644
52 - Waghabi MC, Coutinho-Silva R, Feige JJ, Higuchi Mde L, Becker D, Burnstock G, Araújo-Jorge TC. Gap junction reduction in cardiomyocytes following transforming growth factor-beta treatment and Trypanosoma cruzi infection. Mem Inst Oswaldo Cruz. 2009;104:1083-1090. doi:10.1590/S0074-02762009000800004
53 - Goldenberg RC, Iacobas DA, Iacobas S, Rocha LL, da Silva de Azevedo Fortes F, Vairo L, Nagajyothi F, Campos de Carvalho AC, Tanowitz HB, Spray DC. Transcriptomic alterations in Trypanosoma cruzi-infected cardiac myocytes. Microbes Infect. 2009;11:1140-1149. doi:10.1016/j.micinf.2009.08.009
54 - Adesse D, Goldenberg RC, Fortes FS, Jasmin, Iacobas DA, Iacobas S, Campos de Carvalho AC, de Narareth Meirelles M, Huang H, Soares MB, Tanowitz HB, Garzoni LR, Spray DC. Gap junctions and chagas disease. Adv Parasitol. 2011;76:63-81. doi:10.1016/B978-0-12-385895-5.00003-7
55 - Oloris SC, Mesnil M, Reis VN, Sakai M, Matsuzaki P, Fonseca Ede S, da Silva TC, Avanzo JL, Sinhorini IL, Guerra JL, Costa-Pinto FA, Maiorka PC, Dagli ML. Hepatic granulomas induced by Schistosoma mansoni in mice deficient for connexin 43 present lower cell proliferation and higher collagen content. Life Sci. 2007;80:1228-1235. doi:10.1016/j.lfs.2006.12.030
56 - Alvarez CL, Schachter J, de Sá Pinheiro AA, Silva Lde S, Verstraeten SV, Persechini PM, Schwarzbaum PJ. Regulation of extracellular ATP in human erythrocytes infected with Plasmodium falciparum. PLoS One. 2014;9:e96216. doi:10.1371/journal.pone.0096216
57 - Nzila A, Mberu E, Bray P, Kokwaro G, Winstanley P, Marsh K, Ward S. Chemosensitization of Plasmodium falciparum by probenecid in vitro. Antimicrob Agents Chemother. 2003;47:2108-2112.
58 - Sowunmi A, Fehintola FA, Adedeji AA, Gbotosho GO, Falade CO, Tambo E, Fateye BA, Happi TC, Oduola AM. Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in children. Trop Med Int Health. 2004;9:606-614. doi:10.1128/AAC.47.7.2108-2112.2003
59 - Masseno V, Muriithi S, Nzila A. In vitro chemosensitization of Plasmodium falciparum to antimalarials by verapamil and probenecid. Antimicrob Agents Chemother. 2009;53:3131-3134.
60 - Dahl G, Qiu F, Wang J. The bizarre pharmacology of the ATP release channel pannexin1. Neuropharmacology. 2013;75:583-593. doi:10.1016/j.neuropharm.2013.02.019
61 - Iglesias R, Dahl G, Qiu F, Spray DC, Scemes E. Pannexin 1: the molecular substrate of astrocyte “hemichannels”. J Neurosci. 2009;29:7092-7097. doi:10.1523/JNEUROSCI.6062-08.2009
62 - Mortimer L, Moreau F, Cornick S, Chadee K. The NLRP3 Inflammasome is a pathogen sensor for invasive Entamoeba histolytica via activation of α5β1 integrin at the macrophage-amebae intercellular junction. PLoS Pathog. 2015;11:e1004887. doi:10.1371/journal.ppat.1004887
63 - Li MW, Wang J, Zhao YO, Fikrig E. Innexin AGAP001476 is critical for mediating anti-Plasmodium responses in Anopheles mosquitoes. J Biol Chem. 2014;289:24885-24897. doi:10.1074/jbc.M114.554519
64 - Alkhalil A, Hill DA, Desai SA. Babesia and plasmodia increase host erythrocyte permeability through distinct mechanisms. Cell Microbiol. 2007;9:851-860. doi:10.1111/j.1462-5822.2006.00834.x
65 - Fernandes MC, Cortez M, Flannery AR, Tam C, Mortara RA, Andrews NW. Trypanosoma cruzi subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion. J Exp Med. 2011;208:909-921. doi:10.1084/jem.20102518
66 - Schalper KA, Orellana JA, Berthoud VM, Sáez JC. Dysfunctions of the diffusional membrane pathways mediated hemichannels in inherited and acquired diseases. Curr Vasc Pharmacol. 2009;7:486-505. doi:10.2174/157016109789043937
67 - Costales J, Rowland EC. A role for protease activity and host-cell permeability during the process of Trypanosoma cruzi egress from infected cells. J Parasitol. 2007;93:1350-1359. doi:10.1645/GE-1074.1
68 - Osuna A, Rodríguez-Cabezas MN, Castanys S, Mesa-Valle MC, Mascaro MC. A protein secreted by Trypanosoma cruzi capable of inducing the entry of inert particles into HeLa cells. Int J Parasitol. 1995;25:1213-1225.
69 - Rossi MA, Silva JS. Permeability alteration of the sarcolemmal membrane, particularly at the site of macrophage contact, in experimental chronic Trypanosoma cruzi myocarditis in mice. Int J Exp Pathol. 1990;71:545-555.
70 - Cabantchik ZI. Altered membrane transport of malaria-infected erythrocytes: a possible pharmacologic target. Blood. 1989;74:1464-1471.
71 - Ginsberg H. Alterations caused by the intraerythrocytic malaria parasite in the permeability of its host cell membrane. Comp Biochem Physiol. 1990;95:31-39.
72 - Orellana JA, Schalper KA, Figueroa V, Sanchez H, Sáez JC. Regulation of intercellular calcium signaling through calcium interactions with connexin-based channels. Adv Exp Med Biol. 2012;740:777-794. doi:10.1007/978-94-007-2888-2_34
73 - Sanchez HA, Orellana JA, Verselis VK, Sáez JC. Metabolic inhibition increases activity of connexin-32 hemichannels permeable to Ca2+ in transfected HeLa cells. Am J Physiol Cell Physiol. 2009;297:C665-C678. doi:10.1152/ajpcell.00200.2009
74 - Sanchez HA, Mese G, Srinivas M, White TW, Verselis VK. Differentially altered Ca2+ regulation and Ca2+ permeability in C x 26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome. J Gen Physiol. 2010;136:47-62. doi:10.1085/jgp.201010433
75 - Schalper KA, Sanchez HA, Lee SC, Altenberg GA, Nathanson MH, Saez JC. Connexin 43 hemichannels mediate the Ca2+ influx induced by extracellular alkalinization. Am J Physiol Cell Physiol. 2010;299:C1504-C1515. doi:10.1152/ajpcell.00015.2010
76 - Fiori MC, Figueroa V, Zoghbi ME, Saez JC, Reuss L. Permeation of calcium through purifed Connexin 26 hemichannels. J Biol Chem. 2012;287:40826-40834. doi:10.1074/jbc.M112.383281
77 - Moreno SN, Silva J, Vercesi AE, Docampo R. Cytosolic-free calcium elevation in Trypanosoma cruzi is required for cell invasion. J Exp Med. 1994;180:1535-1540. doi:10.1084/jem.180.4.1535
78 - Tardieux I, Nathanson MH, Andrews NW. Role in host cell invasion of Trypanosoma cruzi-induced cytosolic-free Ca2+ transients. J Exp Med. 1994;179:1017-1022. doi:10.1084/jem.179.3.1017
79 - Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, in ammation, and associated diseases. Annu Rev Immunol. 2011;29:707-735. doi:10.1146/annurev-immunol-031210-101405