Pathways and Signaling Crosstalk with Oxidant in Calcium Influx in Airway Smooth Muscle Cells

  • Lei Cai
  • Qinghua HuEmail author


Influx of extracellular calcium through calcium channels in the plasma membrane contributes to the sustained phase of [Ca2+]i elevation following agonist stimulation. The interactions between channel proteins like TRPC, STIM1, and Orai1, as well as protein and regulatory molecules including reactive oxygen species (ROSs), have been shown to be involved in the opening of calcium entry channels. The contribution of endogenous hydrogen peroxide (H2O2) to agonist-induced intracellular calcium oscillation was first reported as early as 2002 in vascular endothelial cells. While both the receptor-operated calcium channel and store-operated calcium channel proteins possess cysteine residues, they could also be potential targets of ROSs. Mitochondria-derived H2O2 was shown to work as a cofactor together with STIM1 to mediate histamine-stimulated Ca2+ influx in airway smooth muscle cells. Furthermore, intracellular ROSs can interact with members of transient receptor potential (TRP) superfamilies and contribute to Ca2+ influx. ROS-induced TRP intracellular translocation has been suggested as a critical underlying mechanism of TRP activation, which could be a clue to explain how intracellular ROSs cooperate with STIM1 to mediate Ca2+ influx. The cooperation of ROSs and calcium signaling has magnified physiological or pathological effects.


Oxidant Cooperation Calcium influx 



intracellular calcium concentration


airway smooth muscle cell


sarcoplasmic reticulum


inositol 1,4,5-trisphosphate


reactive oxygen species


voltage-dependent calcium channels


receptor-operated calcium channel


store-operated calcium channel


capacitative Ca2+ entry


phosphatidylinositol biphosphate




calcium-release-activated calcium current


transient receptor potential


stromal interaction molecule


TRP canonical




Ca2+ release-activated channel


severe combined immune deficiency


nicotinamide adenine dinucleotide phosphate


reactive nitrogen species


ryanodine receptor


mitochondrial DNA


ethidium bromide


insulin-like growth factor 1


endothelial growth factor


arginine vasopressin


vascular cell adhesion molecule


  1. 1.
    Sanders KM (2001) Invited review: mechanisms of calcium handling in smooth muscles. J Appl Physiol 91: 1438–1449.PubMedGoogle Scholar
  2. 2.
    Worley JF, 3rd, Kotlikoff MI (1990) Dihydropyridine-sensitive single calcium channels in airway smooth muscle cells. Am J Physiol 259: L468–480.PubMedGoogle Scholar
  3. 3.
    Murray RK, Kotlikoff MI (1991) Receptor-activated calcium influx in human airway smooth muscle cells. J Physiol 435: 123–144.PubMedGoogle Scholar
  4. 4.
    Parekh AB, Penner R (1997) Store depletion and calcium influx. Physiol Rev 77: 901–930.PubMedGoogle Scholar
  5. 5.
    Cheng KT, Ong HL, Liu X, Ambudkar IS (2011) Contribution of TRPC1 and Orai1 to Ca2+ entry activated by store depletion. Adv Exp Med Biol 704: 435–449.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen T, Zhu L, Wang T, Ye H, Huang K, et al. Mitochondria depletion abolishes agonist-induced Ca2+ plateau in airway smooth muscle cells: potential role of H2O2. Am J Physiol Lung Cell Mol Physiol 298: L178–188.Google Scholar
  7. 7.
    Croxton TL, Fleming C, Hirshman CA (1994) Expression of dihydropyridine resistance differs in porcine bronchial and tracheal smooth muscle. Am J Physiol 267: L106–112.PubMedGoogle Scholar
  8. 8.
    Janssen LJ (1997) T-type and L-type Ca2+ currents in canine bronchial smooth muscle: characterization and physiological roles. Am J Physiol 272: C1757–1765.PubMedGoogle Scholar
  9. 9.
    Janssen LJ, Daniel EE (1991) Depolarizing agents induce oscillations in canine bronchial smooth muscle membrane potential: possible mechanisms. J Pharmacol Exp Ther 259: 110–117.PubMedGoogle Scholar
  10. 10.
    Hall IP (2000) Second messengers, ion channels and pharmacology of airway smooth muscle. Eur Respir J 15: 1120–1127.PubMedCrossRefGoogle Scholar
  11. 11.
    Bolton TB (1979) Mechanisms of action of transmitters and other substances on smooth muscle. Physiol Rev 59: 606–718.PubMedGoogle Scholar
  12. 12.
    Van Breemen C, Aaronson P, Loutzenhiser R (1978) Sodium-calcium interactions in mammalian smooth muscle. Pharmacol Rev 30: 167–208.PubMedGoogle Scholar
  13. 13.
    de la Fuente G, Palacios O, Villagra E, Villanueva ME (1995) Isolation of Coxsackieviruses B5 in a fatal case of meningoencephalitis. Rev Med Chil 123: 1510–1513.PubMedGoogle Scholar
  14. 14.
    Putney JW, Jr. (1986) A model for receptor-regulated calcium entry. Cell Calcium 7: 1–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Casteels R, Droogmans G (1981) Exchange characteristics of the noradrenaline-sensitive calcium store in vascular smooth muscle cells or rabbit ear artery. J Physiol 317: 263–279.PubMedGoogle Scholar
  16. 16.
    Ito S, Kume H, Naruse K, Kondo M, Takeda N, et al. (2008) A novel Ca2+ influx pathway activated by mechanical stretch in human airway smooth muscle cells. Am J Respir Cell Mol Biol 38: 407–413.PubMedCrossRefGoogle Scholar
  17. 17.
    Gosling M, Poll C, Li S (2005) TRP channels in airway smooth muscle as therapeutic targets. Naunyn Schmiedebergs Arch Pharmacol 371: 277–284.PubMedCrossRefGoogle Scholar
  18. 18.
    Corteling RL, Li S, Giddings J, Westwick J, Poll C, et al. (2004) Expression of transient receptor potential C6 and related transient receptor potential family members in human airway smooth muscle and lung tissue. Am J Respir Cell Mol Biol 30: 145–154.PubMedCrossRefGoogle Scholar
  19. 19.
    Jia Y, Wang X, Varty L, Rizzo CA, Yang R, et al. (2004) Functional TRPV4 channels are expressed in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 287: L272–278.PubMedCrossRefGoogle Scholar
  20. 20.
    White TA, Xue A, Chini EN, Thompson M, Sieck GC, et al. (2006) Role of transient receptor potential C3 in TNF-alpha-enhanced calcium influx in human airway myocytes. Am J Respir Cell Mol Biol 35: 243–251.PubMedCrossRefGoogle Scholar
  21. 21.
    Perez-Zoghbi JF, Karner C, Ito S, Shepherd M, Alrashdan Y, et al. (2009) Ion channel regulation of intracellular calcium and airway smooth muscle function. Pulm Pharmacol Ther 22: 388–397.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, et al. (2005) STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437: 902–905.PubMedCrossRefGoogle Scholar
  23. 23.
    Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, et al. (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169: 435–445.PubMedCrossRefGoogle Scholar
  24. 24.
    Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, et al. (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441: 179–185.PubMedCrossRefGoogle Scholar
  25. 25.
    Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, et al. (2006) A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441: 646–650.PubMedCrossRefGoogle Scholar
  26. 26.
    Hogan PG, Lewis RS, Rao A Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol 28: 491–533.Google Scholar
  27. 27.
    Cheng KT, Liu X, Ong HL, Ambudkar IS (2008) Functional requirement for Orai1 in store-operated TRPC1-STIM1 channels. J Biol Chem 283: 12935–12940.PubMedCrossRefGoogle Scholar
  28. 28.
    Huang GN, Zeng W, Kim JY, Yuan JP, Han L, et al. (2006) STIM1 carboxyl-terminus activates native SOC, Icrac and TRPC1 channels. Nat Cell Biol 8: 1003–1010.PubMedCrossRefGoogle Scholar
  29. 29.
    Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, et al. (2007) Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components. J Biol Chem 282: 9105–9116.PubMedCrossRefGoogle Scholar
  30. 30.
    Lopez JJ, Salido GM, Pariente JA, Rosado JA (2006) Interaction of STIM1 with endogenously expressed human canonical TRP1 upon depletion of intracellular Ca2+ stores. J Biol Chem 281: 28254–28264.PubMedCrossRefGoogle Scholar
  31. 31.
    Yuan JP, Zeng W, Huang GN, Worley PF, Muallem S (2007) STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat Cell Biol 9: 636–645.PubMedCrossRefGoogle Scholar
  32. 32.
    Zeng W, Yuan JP, Kim MS, Choi YJ, Huang GN, et al. (2008) STIM1 gates TRPC channels, but not Orai1, by electrostatic interaction. Mol Cell 32: 439–448.PubMedCrossRefGoogle Scholar
  33. 33.
    Jardin I, Lopez JJ, Salido GM, Rosado JA (2008) Orai1 mediates the interaction between STIM1 and hTRPC1 and regulates the mode of activation of hTRPC1-forming Ca2+ channels. J Biol Chem 283: 25296–25304.PubMedCrossRefGoogle Scholar
  34. 34.
    Liao Y, Erxleben C, Yildirim E, Abramowitz J, Armstrong DL, et al. (2007) Orai proteins interact with TRPC channels and confer responsiveness to store depletion. Proc Natl Acad Sci U S A 104: 4682–4687.PubMedCrossRefGoogle Scholar
  35. 35.
    Hu Q, Yu ZX, Ferrans VJ, Takeda K, Irani K, et al. (2002) Critical role of NADPH oxidase-derived reactive oxygen species in generating Ca2+ oscillations in human aortic endothelial cells stimulated by histamine. J Biol Chem 277: 32546–32551.PubMedCrossRefGoogle Scholar
  36. 36.
    Hidalgo C, Donoso P (2008) Crosstalk between calcium and redox signaling: from molecular mechanisms to health implications. Antioxid Redox Signal 10: 1275–1312.PubMedCrossRefGoogle Scholar
  37. 37.
    Bootman MD, Taylor CW, Berridge MJ (1992) The thiol reagent, thimerosal, evokes Ca2+ spikes in HeLa cells by sensitizing the inositol 1,4,5-trisphosphate receptor. J Biol Chem 267: 25113–25119.PubMedGoogle Scholar
  38. 38.
    Hu Q, Zheng G, Zweier JL, Deshpande S, Irani K, et al. (2000) NADPH oxidase activation increases the sensitivity of intracellular Ca2+ stores to inositol 1,4,5-trisphosphate in human endothelial cells. J Biol Chem 275: 15749–15757.PubMedCrossRefGoogle Scholar
  39. 39.
    Du W, Frazier M, McMahon TJ, Eu JP (2005) Redox activation of intracellular calcium release channels (ryanodine receptors) in the sustained phase of hypoxia-induced pulmonary vasoconstriction. Chest 128: 556S-558S.PubMedCrossRefGoogle Scholar
  40. 40.
    Xi Q, Cheranov SY, Jaggar JH (2005) Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca2+ sparks. Circ Res 97: 354–362.PubMedCrossRefGoogle Scholar
  41. 41.
    Sun J, Xin C, Eu JP, Stamler JS, Meissner G (2001) Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO. Proc Natl Acad Sci U S A 98: 11158–11162.PubMedCrossRefGoogle Scholar
  42. 42.
    Xu L, Eu JP, Meissner G, Stamler JS (1998) Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science 279: 234–237.PubMedCrossRefGoogle Scholar
  43. 43.
    Porter Moore C, Zhang JZ, Hamilton SL (1999) A role for cysteine 3635 of RYR1 in redox modulation and calmodulin binding. J Biol Chem 274: 36831–36834.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang JZ, Wu Y, Williams BY, Rodney G, Mandel F, et al. (1999) Oxidation of the skeletal muscle Ca2+ release channel alters calmodulin binding. Am J Physiol 276: C46–53.PubMedGoogle Scholar
  45. 45.
    Espinosa A, Leiva A, Pena M, Muller M, Debandi A, et al. (2006) Myotube depolarization generates reactive oxygen species through NAD(P)H oxidase; ROS-elicited Ca2+ stimulates ERK, CREB, early genes. J Cell Physiol 209: 379–388.PubMedCrossRefGoogle Scholar
  46. 46.
    Kanzaki M, Zhang YQ, Mashima H, Li L, Shibata H, et al. (1999) Translocation of a calcium-permeable cation channel induced by insulin-like growth factor-I. Nat Cell Biol 1: 165–170.PubMedCrossRefGoogle Scholar
  47. 47.
    Cayouette S, Boulay G (2007) Intracellular trafficking of TRP channels. Cell Calcium 42: 225–232.PubMedCrossRefGoogle Scholar
  48. 48.
    Mehta D, Ahmmed GU, Paria BC, Holinstat M, Voyno-Yasenetskaya T, et al. (2003) RhoA interaction with inositol 1,4,5-trisphosphate receptor and transient receptor potential channel-1 regulates Ca2+ entry. Role in signaling increased endothelial permeability. J Biol Chem 278: 33492–33500.Google Scholar
  49. 49.
    Odell AF, Scott JL, Van Helden DF (2005) Epidermal growth factor induces tyrosine phosphorylation, membrane insertion, and activation of transient receptor potential channel 4. J Biol Chem 280: 37974–37987.PubMedCrossRefGoogle Scholar
  50. 50.
    Bezzerides VJ, Ramsey IS, Kotecha S, Greka A, Clapham DE (2004) Rapid vesicular translocation and insertion of TRP channels. Nat Cell Biol 6: 709–720.PubMedCrossRefGoogle Scholar
  51. 51.
    Smyth JT, Lemonnier L, Vazquez G, Bird GS, Putney JW, Jr. (2006) Dissociation of regulated trafficking of TRPC3 channels to the plasma membrane from their activation by phospholipase C. J Biol Chem 281: 11712–11720.PubMedCrossRefGoogle Scholar
  52. 52.
    Cayouette S, Lussier MP, Mathieu EL, Bousquet SM, Boulay G (2004) Exocytotic insertion of TRPC6 channel into the plasma membrane upon Gq protein-coupled receptor activation. J Biol Chem 279: 7241–7246.PubMedCrossRefGoogle Scholar
  53. 53.
    Song MY, Makino A, Yuan JX (2011) Role of reactive oxygen species and redox in regulating the function of transient receptor potential channels. Antioxid Redox Signal 15: 1549–1565.PubMedCrossRefGoogle Scholar
  54. 54.
    Hecquet CM, Ahmmed GU, Vogel SM, Malik AB (2008) Role of TRPM2 channel in mediating H2O2-induced Ca2+ entry and endothelial hyperpermeability. Circ Res 102: 347–355.PubMedCrossRefGoogle Scholar
  55. 55.
    Yoshida T, Inoue R, Morii T, Takahashi N, Yamamoto S, et al. (2006) Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat Chem Biol 2: 596–607.PubMedCrossRefGoogle Scholar
  56. 56.
    Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, et al. (2002) LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9: 163–173.PubMedCrossRefGoogle Scholar
  57. 57.
    Graham S, Ding M, Ding Y, Sours-Brothers S, Luchowski R, et al. (2010) Canonical transient receptor potential 6 (TRPC6), a redox-regulated cation channel. J Biol Chem 285: 23466–23476.PubMedCrossRefGoogle Scholar
  58. 58.
    Ding Y, Winters A, Ding M, Graham S, Akopova I, et al. (2011) Reactive oxygen species-mediated TRPC6 protein activation in vascular myocytes, a mechanism for vasoconstrictor-regulated vascular tone. J Biol Chem 286: 31799–31809.PubMedCrossRefGoogle Scholar
  59. 59.
    Weissmann N, Sydykov A, Kalwa H, Storch U, Fuchs B, et al. (2012) Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice. Nat Commun 3: 649.PubMedCrossRefGoogle Scholar
  60. 60.
    Groschner K, Rosker C, Lukas M (2004) Role of TRP channels in oxidative stress. Novartis Found Symp 258: 222–230; discussion 231–225, 263–226.Google Scholar
  61. 61.
    Groschner K, Hingel S, Lintschinger B, Balzer M, Romanin C, et al. (1998) Trp proteins form store-operated cation channels in human vascular endothelial cells. FEBS Lett 437: 101–106.PubMedCrossRefGoogle Scholar
  62. 62.
    Poteser M, Graziani A, Rosker C, Eder P, Derler I, et al. (2006) TRPC3 and TRPC4 associate to form a redox-sensitive cation channel. Evidence for expression of native TRPC3-TRPC4 heteromeric channels in endothelial cells. J Biol Chem 281: 13588–13595.PubMedCrossRefGoogle Scholar
  63. 63.
    Bae YS, Kang SW, Seo MS, Baines IC, Tekle E, et al. (1997) Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem 272: 217–221.Google Scholar
  64. 64.
    Shimoda LA, Undem C (2010) Interactions between calcium and reactive oxygen species in pulmonary arterial smooth muscle responses to hypoxia. Respir Physiol Neurobiol 174: 221–229.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhu L, Luo Y, Chen T, Chen F, Wang T, et al. (2008) Ca2+ oscillation frequency regulates agonist-stimulated gene expression in vascular endothelial cells. J Cell Sci 121: 2511–2518.PubMedCrossRefGoogle Scholar
  66. 66.
    Zhu L, Song S, Pi Y, Yu Y, She W, et al. Cumulated Ca2+ spike duration underlies Ca2+ oscillation frequency-regulated NFkappaB transcriptional activity. J Cell Sci 124: 2591–2601.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of PathophysiologyTongji Medical College, Huazhong University of Science and TechnologyWuhanPeople’s Republic of China

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