Summary of published works on the effect of parasite infections on the gap junction proteins.
Abstract
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
Gap junction proteins | Parasite | Cell type | Effects | References |
---|---|---|---|---|
Cx43 | Cardiomyocytes | Downregulated | [43] | |
Astrocytes | Downregulated | [44] | ||
Leptomeningeal cells | Downregulated | [44] | ||
Cardiomyocytes | Downregulated | [48] | ||
Cardiomyocytes | Downregulated | [51] | ||
Cardiomyocytes and heart human biopsies | Downregulated | [50] | ||
Astrocytes | Downregulated | [44] | ||
Leptomeningeal cells | Downregulated | [44] | ||
Cx26 | Astrocytes | Downregulated | [44] | |
Cx37 | Heart from chagasic mouse | Upregulated | [52] | |
Cx40 | Heart from chagasic mouse | Not change | [52] | |
Cx45 | Heart from chagasic mouse | Not change | [52] | |
Cardiomyocytes | Upregulated | [51] | ||
Panx1 | Human erythrocytes | Increased ATP release | [54] | |
Human monocytic cells | Increased ATP release | [60] | ||
AGAP001476 | Midgut tissues from | Upregulated | [61] | |
Midgut tissues from | Upregulated | [61] |
Drug | Commercial name | Presentation and quantity | Company | Country production |
---|---|---|---|---|
Probenecid | Probalan | Tablets 500 mg | Lannett | USA |
Probenecid | Probenecid & Colchicine | Tablets 500 mg | Watson | INDIA |
Probenecid | Probenecid | Tablets 500 mg | Mylan | USA |
Probenecid | Probenecid & Colchicine | Tablets 500 mg | Ingenus | USA |
Suramin | Germanin | Vial 1 g | Bayer | Germany |
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].
Abbreviations | Definitions |
---|---|
ATP | Adenosine triphosphate |
cAMP | Cyclic adenosine monophosphate |
CDS | Coding region sequence |
Cx | Connexin |
DCSF | Divalent cation solution free |
HC | Hemichannel |
Inx | Innexin |
Panx | Pannexin |
PMA | Phorbol 12-myristate 13-acetate |
UTR | Untranslated region |
Vinx | Vinnexin |
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
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
3.1.2. Protein expression alterations
At the protein level,
3.1.3. Gene expression regulation
Gene profiling of
3.1.4. Cx knock-out mice and parasitic infections
Hepatic granulomas induced by
3.2. Pannexins (Panxs)
It has been demonstrated that
3.3. Innexins (Inxs)
It has been demonstrated that Inx proteins have a critical role for mediating anti-
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,
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+ [73–76] 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
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.
Acknowledgments
This work was partially supported by FONDECYT grants 11130013 (to JLV) and 1131007 (to JG) and ICM-Economía grant P09-022-F (to JCS).
References
- 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/j.abb.2012.03.008 - 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