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Possible Role of Gap Junction Channels and Non-Junctional Channels in the Infection Caused by Trypanosoma cruzi

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José Luis Vega, Camilo Juyumaya, Luis Rodríguez, Juan Güiza, Camila Gutíerrez, Iván Barría and Juan C. Sáez

Submitted: 02 September 2018 Reviewed: 09 January 2019 Published: 18 December 2019

DOI: 10.5772/intechopen.84278

From the Edited Volume

Biology of Trypanosoma cruzi

Edited by Wanderley De Souza

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Chagas disease affects low-income nations with health consequences that impact the economy of those countries. Interestingly, inhibitors of channels formed by proteins of the gap junction family, such as suramin and boldine, exhibit trypanocidal activity. Gap junction proteins are integral membrane proteins present in both vertebrates and invertebrates that participate in cellular communication. These proteins form gap junction channels, which connect the cytoplasm of neighboring cells or non-junctional channels that connect the intra- and extracellular milieu. Interestingly, Trypanosoma cruzi modulates the expression of proteins of the gap junction family or modify the activity of the channels formed by these proteins in host cells. Moreover, Lucifer yellow microinjected into fibroblast was incorporated into associated trypanosomes of Trypanosoma musculi, suggesting the possibility of direct communication via gap junction channels between them. In this chapter, we summarized the current knowledge about the possible roles of gap junction family proteins in Chagas disease.


  • connexin
  • pannexin
  • innexin
  • hemichannels
  • infection

1. Introduction

Chagas disease affects low-income nations with health consequences that impact the economy of these countries [1]. Research aimed at understanding their biology and identification of potential targets for drug development is the highest priority [1]. Interestingly, inhibitors of channels formed by proteins of the gap junction family such as suramin and boldine have trypanocidal activity and some of them are currently used for treatment of parasitic diseases such Human African Trypanosomiasis [2, 3, 4, 5]. Also, studies have shown that infections caused by Trypanosoma cruzi (T. cruzi) modulate the expression of proteins of the gap junction family or modify the activity of the channels formed by these proteins in host cells [6, 7, 8, 9, 10, 11]. Moreover, previous studies have shown gap junction type structures in Trypanosoma musculi [12]. In this chapter, we summarized the current knowledge about the role of gap junction family proteins in Chagas disease.


2. Gap junction proteins

Gap junction proteins are present in both vertebrates and invertebrates from mesozoa to mammals [13]. The protein families include connexins (Cxs), innexins (Inxs) and pannexins (Panxs) [14, 15]. They are integral membrane proteins that participate in cellular communication playing a relevant role in several physiological processes [15]. In vertebrates, Cxs and Panxs are present, while in invertebrates, only Inxs are present [15]. In humans, 21 and 3 genes encode Cx and Panx proteins, respectively [14]. Most Cx genes contain two exons and an intron of variable length [14]. The Panx1 and Panx2 genes contain 5 exons, while the Panx3 gene contains 4 exons [16]. Moreover, Inx genes have been found in the phylum Arthropoda [17, 18, 19, 20], Nematoda [21], Chordata [22], Annelida [23], Platyhelminthes [24], Cnidaria [25], and Mollusca [26]. In Drosophila melanogaster, the Inx genes have the potential to be differentially spliced [18], while in C. elegans, 15% of genes are found in operons and three pairs of the innexins are polycistronic such as inx-12 and inx-13, inx-16 and inx-17, and inx-21 and inx-22 [27]. Regarding the structure of the protein topology, hydropathy plots of several Inx, Cx and Panx proteins have predicted the presence of four hydrophobic domains with transmembrane spanning regions and the extracellular loops with several highly conserved residues [28]. In contrast, the cytoplasmic loop and the carboxy terminus vary extensively in length and amino acid composition [28].

2.1 Gap junction channels

Cx and Inx proteins form gap junction channels, which connect the cytoplasm of neighboring cells [14, 15]. Moreover, Cx, Panx and Inx proteins form non-junctional channels that connect the intra- and extracellular milieu [14]. Gap junction plaques are formed by a variable number of homo- and/or heterotypic gap junction channels with distinct biophysical characteristics [29]. Structurally, they are formed by oligomers of Cx, Inx, or Panx proteins, which co-oligomerize into the same (homomeric) or mixed (heteromeric) channels [30]. Gap junction channels are essential in several physiologic functions such as electrical conduction between cardiomyocytes [31], development and regeneration of skeletal muscle [32], endocrine gland secretion [33], and ovarian folliculogenesis [34]. Also, they are implicated in pathophysiological conditions such as hereditary deafness [35], cataract [36], and tumorigenesis [37].

Gap junction proteins can also form non-junctional channels, which play important roles as autocrine/paracrine cellular communication pathways [14]. They are permeable to ions and several metabolic and signaling molecules such as glucose, glutamate, glutathione, adenosine, NAD+ (superindice) and ATP among others [14]. It has been proposed that Panxs do not form gap junctions, however, they form plasma membrane channels (named pannexons) with some properties similar to those of the non-junctional channels formed by Inxs or Cxs also called hemichannels [15].

The pannexons are permeable to ATP when are activated with certain stimuli such a low oxygen, mechanical stress, and elevated extracellular potassium ion concentration [38]. Otherwise, the Panx1 channel is selective for chloride ions and exhibits no ATP permeability when stimulated simply by depolarization to positive potentials or the C-terminal is cleaved by proteolysis [38]. Since we found increased Panx1 channel activity and increase in ATP release in cells infected with T. cruzi [11], it suggested that under this condition the Panx1 channel does not undergo proteolysis and adopt the large channel configuration [11, 38]. In addition, it has been described that Panx1-based channels are regulated by mechanical stress [39]. Inx-based hemichannels are activated by increased extracellular potassium ion concentration and by membrane depolarization [40]. Furthermore, Panx1- and Inx-based channels are inhibited by low concentration of carbenoxolone (<5 μM) or high probenecid concentrations (>500 μM) [41, 42].

Moreover, Cx-based hemichannels are regulated by intracellular acidification [43], intracellular Ca2+ [44], intracellular Na+ [45], pro-inflammatory cytokines [46], positive membrane potentials [47], phosphorylation [48], and S-nitrosylation [49]. They are inhibited by lanthanum chloride, carbenoxolone (>50 μM), and Cx mimetic peptides GAP16, GAP27, and GAP19 [15].


3. Gap junction and Chagas

3.1 Connexins

In 1992, Spray’s group showed for the first time that gap junctions were altered between rat neonatal cardiomyocytes infected with the Tulahuen strain of T. cruzi (Table 1) [6]. They showed that junctional conductance and intercellular transfer of Lucifer yellow was reduced between cardiomyocytes infected with T. cruzi (Figure 1) [6]. In 1998, the same group described that Tulahuen strain of T. cruzi reduced gap junction communication between rat astrocytes and between rat leptomeningeal cells as well [7]. Also, these authors demonstrated through immunocytochemistry studies that Cx43 reactivity was significantly reduced in whole brains from rats acutely infected with T. cruzi [7]. In 2008, in vitro studies showed that Y strain of T. cruzi increased the amount of Cx43 at 1 hour postinfection and reduced it at 72 hour postinfection in mouse cardiomyocytes (Figure 1) [8]. Moreover, they demonstrated through immunoblotting analysis that the amount of Cx43 was significantly reduced in heart atria and ventricles from mice infected with Y strain of T. cruzi at 11 days postinfection [8]. In 2009, Waghabi and collaborators demonstrated that the number and length of Cx43 plaques were reduced in heart biopsies of human chronic chagasic patients [9]. In 2013, we described that CL Brener strain of T. cruzi increased the Cx43 hemichannel activity in HeLa cells stably transfected with Cx43 (Figure 1) [15]. Also, we observed that the number of amastigotes was 3 times higher in HeLa-Cx43 as compared to HeLa parental cells at 48 hours postinfection [15]. In 2014, Burke and collaborators demonstrated that Brazil strain of T. cruzi reduced the amount of Cx43 in brown adipose tissue at 30 and 90 days postinfection (Figure 1) [10]. Moreover, T. cruzi infection caused an increased the amount of Cx43 protein in white adipose tissue at 30 and 90 days postinfection [10].

Table 1.

Summary of the studies that describe the effect of T. cruzi on gap junction protein family.

Figure 1.

Model that summarizes the main effects of the Trypanosoma cruzi on cellular communications mediated by gap junction channels. Parasites release a virulence factor that opens Panx1 channels allowing the release of ATP to the extracellular milieu [11]. Also, the parasite causes a reduction of intercellular communications mediated by gap junctions [6]. Contrarily, the parasite increases the activity of the hemichannels present in the plasma membrane of the infected cells [15].

3.2 Pannexins

In 2018, we found that H510 strain of T. cruzi increased the Panx1 channel activity in rat neonatal cardiomyocytes at 1 hour postinfection [11]. Interestingly, the increased pannexon activity induced by the parasite was directly related to an elevated ATP release [11]. This is relevant because ATP has been proposed as a key molecule in T. cruzi host cell invasion [11, 50]. For example, blockade of P2Y1 receptors with a MRS2179, a selective P2Y1 antagonist, reduced T. cruzi-evoked Ca2+ transients in rat cardiomyocytes [11]. Moreover, inhibition of mitochondrial ATP production by treating parasites with rotenone plus antimycin A reduced the infectivity of the parasites [50]. Also, pre-treatment with pannexon activity-blocking drugs significantly reduced the number of intracellular parasites in cardiomyocytes infected with H510 strain of T. cruzi [11]. For instance, cells exposed to 100 μM 10Panx1 or 400 μM probenecid showed a 114 ± 2 and 71 ± 2 parasites/500 cells, respectively, versus 5001 ± 2 parasites/500 cells in control condition [11]. Interestingly, scanning and transmission electron microscopy studies have demonstrated the presence of reminiscent gap junction at physical interactions between Trypanosoma musculi and mice spleen-derived adherent fibroblasts [12]. Also, Lucifer yellow microinjected into fibroblast was incorporated into associated trypanosomes, suggesting that those gap junctions were functional [12].


4. Gap junction channel blocking compounds as antiparasitic drugs

Interestingly, several drugs that block the activity of gap junction channels have been described as potent anti-parasitic agents. Among them are: probenecid, boldine and suramin, among others (Table 2) [2, 3, 4].

Table 2.

Antiparasitic drugs and channel blocker drugs.

4.1 Probenecid

Human clinical trials have shown that probenecid, an inhibitor of a non-junctional channel formed by Panx1 has an antimalarial effect [2]. The authors described that 50 μM probenecid caused an increase in the sensitivity of highly resistant V1S strain of Plasmodium falciparum to pyrimethamine, sulfadoxine, chlorcycloguanil, and dapsone by seven-, five-, three-, and three-folds, respectively [2].

4.2 Suramin

Suramin, a general antagonist of purinergic receptors (P2Y and P2X) [51] and blocker of Panx1 channels [52], exhibits anti-parasitic properties [3]. Culture of LLC-MK2 cells treated with suramin (500 μM) during the intracellular development of T. cruzi, caused morphological changes in the parasites; increase in parasite width, and partial or complete detachment between flagella and cell body [3]. Interestingly, suramin is one of the 5 approved drugs for treatment of sleeping sickness [5].

4.3 Boldine

Boldine, an alkaloid obtained from Boldo tree, which blocks the activity of Cx43-formed hemichannels, and Panx1 hemichannels exhibit, an anti-parasitic activity [53, 54]. Boldine at concentrations above 500 μM reduces the epimastigotes growth of Tulahuen, LQ and DM28c strains of T. cruzi [4]. Since the active compound also inhibited cell respiration, it was suggested that these drugs may block the mitochondrial electron transport [4].


5. Conclusions

Chagas diseases affect predominantly underprivileged areas of Latin America, but attention has been increasing lately due to the rise in people migration habits, intercontinental travels, and immune suppressed patients [1]. Unfortunately, current therapeutic options include only two compounds (nifurtimox and benznidazole) with considerable toxicity and side effects, so the new drug development is of the highest priority [1]. Hemichannels are involved in the regulation of plasma membrane permeability in ischemic insults or metabolic inhibition [55, 56]. Moreover, alterations of plasma membrane is a common phenomenon in parasite-induced infections such malaria and T. cruzi, among others [57, 58]. Thus, hemichannels could be key players in parasite-induced plasma membrane permeabilization. All the above data support the importance of studying the possible role of hemichannels in parasitic infections. They could be potential targets for the development of new compounds to limit parasite infections or tissue/organ damage induced by their presence.



This work was partially supported by a MINEDUC-UA project code ANT 1755 (to JLV), Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) 1150291 (to JCS) and ICM-Economía P09-022-F Centro Interdisciplinario de Neurociencias de Valparaíso (to JCS). JG and IB hold a CONICYT-Ph.D. fellowship, Chile.


Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


  1. 1. Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375:1388-1402. DOI: 10.1016/S0140-6736(10)60061-X
  2. 2. Masseno V, Muriithi S, Nzila A. In vitro chemosensitization of Plasmodium falciparum to antimalarials by verapamil and probenecid. Antimicrobial Agents and Chemotherapy. 2009;53:3131-3134. DOI: 10.1128/AAC.01689-08
  3. 3. 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 Tropica. 2006;98:162-175. DOI: 10.1016/j.actatropica.2006.04.003
  4. 4. Morello A, Lipchenca I, Cassels BK, Speisky H, Aldunate J, Repetto Y. Trypanocidal effect of boldine and related alkaloids upon several strains of Trypanosoma cruzi. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology. 1994;107:367-371. DOI: 10.1016/1367-8280(94)90063-9
  5. 5. Singh Grewal A, Pandita D, Bhardwaj S, Lather V. Recent updates on development of drug molecules for human African trypanosomiasis. Current Topics in Medicinal Chemistry. 2016;16(20):2245-2265
  6. 6. de Carvalho AC, Tanowitz HB, Wittner M, Dermietzel R, Roy C, Hertzberg EL, et al. Gap junction distribution is altered between cardiac myocytes infected with Trypanosoma cruzi. Circulation Research. 1992;70:733-742
  7. 7. Campos de Carvalho AC, Roy C, Hertzberg EL, Tanowitz HB, Kessler JA, Weiss LM, et al. Gap junction disappearance in astrocytes and leptomeningeal cells as a consequence of protozoan infection. Brain Research. 1998;790:304-314. DOI: 10.1016/S0006-8993(97)01523-0
  8. 8. Adesse D, Garzoni LR, Huang H, Tanowitz HB, de Nazareth MM, Spray DC. Trypanosoma cruzi induces changes in cardiac connexin43 expression. Microbes and Infection. 2008;10:21-28. DOI: 10.1016/j.micinf.2007.09.017
  9. 9. Waghabi MC, Coutinho-Silva R, Feige JJ, Higuchi Mde L, Becker D, Burnstock G, et al. Gap junction reduction in cardiomyocytes following transforming growth factor-beta treatment and Trypanosoma cruzi infection. Memórias do Instituto Oswaldo Cruz. 2009;104:1083-1090. DOI: 10.1590/S0074-02762009000800004
  10. 10. Burke S, Nagajyothi F, Thi MM, Hanani M, Scherer PE, Tanowitz HB, et al. Adipocytes in both brown and white adipose tissue of adult mice are functionally connected via gap junctions: Implications for Chagas disease. Microbes and Infection. 2014;16:893-901. DOI: 10.1016/j.micinf.2014.08.006
  11. 11. Barría I, Güiza J, Cifuentes F, Zamorano P, Sáez JC, González J, et al. Trypanosoma cruzi infection induces pannexin-1 channel opening in cardiac myocytes. The American Journal of Tropical Medicine and Hygiene. 2018;98:105-112. DOI: 10.4269/ajtmh.17-0293
  12. 12. Gugssa A, Lee CM, Gebru S, Desta D, Murray S, Baccetti B, et al. Co-culture of Trypanosoma musculi with spleen-derived adherent fibroblasts: Possible transfer of small molecules via connexons. Journal of Submicroscopic Cytology and Pathology. 2005;37:223-229
  13. 13. Meşe G, Richard G, White TW. Gap junctions: Basic structure and function. The Journal of Investigative Dermatology. 2007;127:2516-2524. DOI: 10.1038/sj.jid.5700770
  14. 14. Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC. Plasma membrane channels formed by connexins: Their regulation and functions. Physiological Reviews. 2003;83:1359-1400. DOI: 10.1152/physrev.00007.2003
  15. 15. Vega JL, Subiabre M, Figueroa F, Schalper KA, Osorio L, González J, et al. Role of gap junctions and hemichannels in parasitic infections. BioMed Research International. 2013;2013:589130. DOI: 10.1155/2013/589130
  16. 16. Baranova A, Ivanov D, Petrash N, Pestova A, Skoblov M, Kelmanson I, et al. 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. 17. Ganfornina MD, Sánchez D, Herrera M, Bastiani MJ. Developmental expression and molecular characterization of two gap junction channel proteins expressed during embryogenesis in the grasshopper Schistocerca americana. Developmental Genetics. 1999;24:137-150. DOI: 10.1002/(SICI)1520-6408(1999)24:1/2<137::AID-DVG13>3.0.CO;2-7
  18. 18. Stebbings LA, Todman MG, Phillips R, Greer CE, Tam J, Phelan P, et al. Gap junctions in Drosophila: Developmental expression of the entire innexin gene family. Mechanisms of Development. 2002;113:197-205. DOI: 10.1016/S0925-4773(02)00025-4
  19. 19. Hong SM, Kang SW, Goo TW, Kim NS, Lee JS, Kim KA, et al. Two gap junction channel (innexin) genes of the Bombyx mori and their expression. Journal of Insect Physiology. 2008;54:180-191. DOI: 10.1016/j.jinsphys.2007.09.002
  20. 20. Calkins TL, Woods-Acevedo MA, Hildebrandt O, Piermarini PM. The molecular and immunochemical expression of innexins in the yellow fever mosquito, Aedes aegypti: Insights into putative life stage- and tissue-specific functions of gap junctions. Comparative Biochemistry and Physiology Part B: Biochemistry & Molecular Biology. 2015;183:11-21. DOI: 10.1016/j.cbpb.2014.11.013
  21. 21. Altun Z, Chen B, Wang Z, Hall D. High resolution map of Caenorhabditis elegans gap junction proteins. Developmental Dynamics. 2009;238:1936-1950. DOI: 10.1002/dvdy.22025
  22. 22. White T, Wang H, Mui R, Litteral J, Brink P. Cloning and functional expression of invertebrate connexins from Halocynthia pyriformis. FEBS Letters. 2004;577:42-48. DOI: 10.1016/j.febslet.2004.09.071
  23. 23. Kandarian B, Sethi J, Wu A, Baker M, Yazdani N, Kym E, et al. The medicinal leech genome encodes 21 innexin genes: Different combinations are expressed by identified central neurons. Development Genes and Evolution. 2012;222:29-44. DOI: 10.1007/s00427-011-0387-z
  24. 24. Zurabian R, Landa A, Robert L, Willms K. Immunolocalization of Taenia solium gap junction innexins. Parasitology. 2008;135:1125-1131. DOI: 10.1017/S0031182008004629
  25. 25. Takaku Y, Hwang JS, Wolf A, Böttger A, Shimizu H, David CN, et al. Innexin gap junctions in nerve cells coordinate spontaneous contractile behavior in Hydra polyps. Scientific Reports. 2014;4:3573. DOI: 10.1038/srep03573
  26. 26. Kelmanson IV, Shagin DA, Usman N, Matz MV, Lukyanov SA, Panchin YV. Altering electrical connections in the nervous system of the pteropod mollusc Clione limacina by neuronal injections of gap junction mRNA. The European Journal of Neuroscience. 2002;16:2475-2476. DOI: 10.1046/j.1460-9568.2002.02423.x
  27. 27. Simonsen K, Moerman D, Naus C. Gap junctions in C. elegans. Frontiers in Physiology. 2014;5:40. DOI: 10.3389/fphys.2014.00040
  28. 28. Phelan P. Innexins: Members of an evolutionarily conserved family of gap-junction proteins. Biochimica et Biophysica Acta - Biomembranes. 2005;1711:225-245. DOI: 10.1016/j.bbamem.2004.10.004
  29. 29. Barbe MT, Monyer H, Bruzzone R. Cell-cell communication beyond connexins: The pannexin channels. Physiology (Bethesda). 2006;21:103-114. DOI: 10.1152/physiol.00048.2005
  30. 30. Falk MM, Buehler LK, Kumar NM, Gilula NB. Cell-free synthesis and assembly of connexins into functional gap junction membrane channels. The EMBO Journal. 1997;16:2703-2716. DOI: 10.1093/emboj/16.10.2703
  31. 31. Kanno S, Saffitz JE. The role of myocardial gap junctions in electrical conduction and arrhythmogenesis. Cardiovascular Pathology. 2001;10:169-177. DOI: 10.1016/S1054-8807(01)00078-3
  32. 32. Araya R, Eckardt D, Maxeiner S, Krüger O, Theis M, Willecke K, et al. Expression of connexins during differentiation and regeneration of skeletal muscle: Functional relevance of connexin43. Journal of Cell Science. 2005;118:27-37. DOI: 10.1242/jcs.01553
  33. 33. Murray SA, Davis K, Gay V. ACTH and adrenocortical gap junctions. Microscopy Research and Technique. 2003;61:240-246. DOI: 10.1002/jemt.10332
  34. 34. Gershon E, Plaks V, Dekel N. Gap junctions in the ovary: Expression, localization and function. Molecular and Cellular Endocrinology. 2008;282:18-25. DOI: 10.1016/j.mce.2007.11.001
  35. 35. Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997;387:80-83. DOI: 10.1038/387080a0
  36. 36. 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
  37. 37. Naus CC, Laird DW. Implications and challenges of connexin connections to cancer. Nature Reviews Cancer. 2010;10:435-441. DOI: 10.1038/nrc2841
  38. 38. Wang J, Dahl G. Pannexin1: A multifunction and multiconductance and/or permeability membrane channel. American Journal of Physiology-Cell Physiology. 2018;315:C290-C299. DOI: 10.1152/ajpcell.00302.2017
  39. 39. Bao L, Locovei S, Dahl G. Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Letters. 2004;572:565-568. DOI: 10.1016/j.febslet.2004.07.009
  40. 40. Dahl G, Muller KJ. Innexin and pannexin channels and their signaling. FEBS Letters. 2014;588:1396-1402. DOI: 10.1016/j.febslet.2014.03.007
  41. 41. Bao L, Samuels S, Locovei S, Macagno ER, Muller KJ, Dahl G. Innexins form two types of channels. FEBS Letters. 2007;581:5703-5708. DOI: 10.1016/j.febslet.2007.11.030
  42. 42. Locovei S, Bao L, Dahl G. Pannexin 1 in erythrocytes: Function without a gap. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:7655-7659. DOI: 10.1073/pnas.0601037103
  43. 43. Delmar M, Coombs W, Sorgen P, Duffy HS, Taffet SM. Structural bases for the chemical regulation of Connexin43 channels. Cardiovascular Research. 2004;62:268-275. DOI: 10.1016/j.cardiores.2003.12.030
  44. 44. Lopez W, Gonzalez J, Liu Y, Harris AL, Contreras JE. Insights on the mechanisms of Ca(2+) regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N/Y). The Journal of General Physiology. 2013;142:23-35. DOI: 10.1085/jgp.201210893
  45. 45. Li F, Sugishita K, Su Z, Ueda I, Barry WH. Activation of connexin-43 hemichannels can elevate [Ca(2+)]i and [Na(+)]i in rabbit ventricular myocytes during metabolic inhibition. Journal of Molecular and Cellular Cardiology. 2001;33:2145-2155. DOI: 10.1006/jmcc.2001.1477
  46. 46. Retamal MA, Froger N, Palacios-Prado N, Ezan P, Sáez PJ, Sáez JC, et al. Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia. The Journal of Neuroscience. 2007;27:13781-13792. DOI: 10.1523/JNEUROSCI.2042-07.2007
  47. 47. Contreras JE, Saez JC, Bukauskas FF, Bennett MV. Gating and regulation of connexin 43 (Cx43) hemichannels. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:11388-11393. DOI: 10.1073/pnas.1434298100
  48. 48. Pogoda K, Kameritsch P, Retamal M, Vega JL. Regulation of gap junction channels and hemichannels by phosphorylation and redox changes: A revision. BMC Cell Biology. 2016;17(Suppl 1):11. DOI: 10.1186/s12860-016-0099-3
  49. 49. Retamal MA, Cortes CJ, Reuss L, Bennett MV, Saez JC. S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: Induction by oxidant stress and reversal by reducing agents. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:4475-4480. DOI: 10.1073/pnas.0511118103
  50. 50. Martins RM, Covarrubias C, Rojas RG, Silber AM, Yoshida N. Use of L-proline and ATP production by Trypanosoma cruzi metacyclic forms as requirements for host cell invasion. Infection and Immunity. 2009;77:3023-3032. DOI: 10.1128/IAI.00138-09
  51. 51. Voogd TE, Vansterkenburg EL, Wilting J, Janssen LH. Recent research on the biological activity of suramin. Pharmacological Reviews. 1993;45:177-203
  52. 52. Qiu F, Dahl G. A permeant regulating its permeation pore: Inhibition of pannexin 1 channels by ATP. American Journal of Physiology-Cell Physiology. 2009;296:C250-C255. DOI: 10.1152/ajpcell.00433.2008
  53. 53. Hernández-Salinas R, Vielma AZ, Arismendi MN, Boric MP, Sáez JC, Velarde V. Boldine prevents renal alterations in diabetic rats. Journal Diabetes Research. 2013;2013:593672. DOI: 10.1155/2013/593672
  54. 54. Yi C, Ezan P, Fernández P, Schmitt J, Sáez JC, Giaume C, et al. Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer’s disease. Glia. 2017;65:1607-1625. DOI: 10.1002/glia.23182
  55. 55. Contreras JE, Sánchez HA, Eugenin EA, Speidel D, Theis M, Willecke K, et al. Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proceedings of the National Academy of Sciences of the United States of America. 2002;99:495-500. DOI: 10.1073/pnas.012589799
  56. 56. Thompson RJ, Zhou N, MacVicar BA. Ischemia opens neuronal gap junction hemichannels. Science. 2006;312:924-927. DOI: 10.1126/science.1126241
  57. 57. Ginsberg H. Alterations caused by the intraerythrocytic malaria parasite in the permeability of its host cell membrane. Comparative Biochemistry and Physiology Part A: Comparative Physiology. 1990;95:31-39. DOI: 10.1016/0300-9629(90)90006-E
  58. 58. Fernandes MC, Andrews NW. Host cell invasion by Trypanosoma cruzi: A unique strategy that promotes persistence. FEMS Microbiology Reviews. 2012;36:734-747. DOI: 10.1111/j.1574-6976.2012.00333.x

Written By

José Luis Vega, Camilo Juyumaya, Luis Rodríguez, Juan Güiza, Camila Gutíerrez, Iván Barría and Juan C. Sáez

Submitted: 02 September 2018 Reviewed: 09 January 2019 Published: 18 December 2019