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The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca2+ release channels

  • Ion Channels, Receptors and Transporters
  • Published:
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Abstract

In this review, we describe the background and implications of our recent discovery that two-pore channels (TPCs) comprise a novel class of calcium release channels gated by the intracellular messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Their localisation to the endolysosomal system highlights a new function for these organelles as targets for NAADP-mediated Ca2+ mobilisation. In addition, we describe how TPCs may also trigger further Ca2+ release by coupling to the endoplasmic reticular stores through activation of IP3 receptors and ryanodine receptors.

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References

  1. Anderson PA, Greenberg RM (2001) Phylogeny of ion channels: clues to structure and function. Comp Biochem Physiol B Biochem Mol Biol 129:17–28

    Article  PubMed  CAS  Google Scholar 

  2. Berg I, Potter BV, Mayr GW, Guse AH (2000) Nicotinic acid adenine dinucleotide phosphate (NAADP+) is an essential regulator of T-lymphocyte Ca2+-signaling. J Cell Biol 150:581–588

    Article  PubMed  CAS  Google Scholar 

  3. Berridge G, Dickinson G, Parrington J, Galione A, Patel S (2002) Solubilization of receptors for the novel Ca2+-mobilizing messenger, nicotinic acid adenine dinucleotide phosphate. J Biol Chem 277:43717–43723

    Article  PubMed  CAS  Google Scholar 

  4. Boittin FX, Galione A, Evans AM (2002) Nicotinic acid adenine dinucleotide phosphate mediates Ca2+ signals and contraction in arterial smooth muscle via a two-pool mechanism. Circ Res 91:1168–1175

    Article  PubMed  CAS  Google Scholar 

  5. Brailoiu E, Churamani D, Pandey V, Brailoiu GC, Tuluc F, Patel S, Dun NJ (2006) Messenger-specific role for nicotinic acid adenine dinucleotide phosphate in neuronal differentiation. J Biol Chem 281:15923–15928

    Article  PubMed  CAS  Google Scholar 

  6. Brailoiu E, Patel S, Dun NJ (2003) Modulation of spontaneous transmitter release from the frog neuromuscular junction by interacting intracellular Ca2+ stores: critical role for nicotinic acid adenine dinucleotide phosphate (NAADP). Biochem J 373:313–318

    Article  PubMed  CAS  Google Scholar 

  7. Brailoiu GC, Brailoiu E, Parkesh R, Galione A, Churchill GC, Patel S, Dun NJ (2009) NAADP-mediated channel “chatter” in neurons of the rat medulla oblongata. Biochem J 419:91–97

    Article  PubMed  CAS  Google Scholar 

  8. Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, Zhu MX (2009) NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature (in press)

  9. Cancela JM, Churchill GC, Galione A (1999) Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells. Nature 398:74–76

    Article  PubMed  CAS  Google Scholar 

  10. Chini EN, Dousa TP (1996) Nicotinate-adenine dinucleotide phosphate-induced Ca2+-release does not behave as a Ca2+-induced Ca2+-release system. Biochem J 316:709–711

    PubMed  CAS  Google Scholar 

  11. Churchill GC, Galione A (2000) Spatial control of Ca2+ signaling by nicotinic acid adenine dinucleotide phosphate diffusion and gradients. J Biol Chem 275:38687–38692

    Article  PubMed  CAS  Google Scholar 

  12. Churchill GC, Galione A (2001) NAADP induces Ca2+ oscillations via a two-pool mechanism by priming IP3- and cADPR-sensitive Ca2+ stores. EMBO J 20:2666–2671

    Article  PubMed  CAS  Google Scholar 

  13. Churchill GC, O’Neill JS, Masgrau R, Patel S, Thomas JM, Genazzani AA, Galione A (2003) Sperm deliver a new second messenger: NAADP. Curr Biol 13:125–128

    Article  PubMed  CAS  Google Scholar 

  14. Churchill GC, Okada Y, Thomas JM, Genazzani AA, Patel S, Galione A (2002) NAADP mobilizes Ca2+ from reserve granules, a lysosome-related organelle, in sea urchin eggs. Cell 111:703–708

    Article  PubMed  CAS  Google Scholar 

  15. Clapper DL, Walseth TF, Dargie PJ, Lee HC (1987) Pyridine nucleotide metabolites stimulate calcium release from sea urchin egg microsomes desensitized to inositol trisphosphate. J Biol Chem 262:9561–9568

    PubMed  CAS  Google Scholar 

  16. Dammermann W, Guse AH (2005) Functional ryanodine receptor expression is required for NAADP-mediated local Ca2+ signaling in T-lymphocytes. J Biol Chem 280:21394–21399

    Article  PubMed  CAS  Google Scholar 

  17. Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H (2008) The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455:992–996

    Article  PubMed  CAS  Google Scholar 

  18. Galione A (2006) NAADP, a new intracellular messenger that mobilizes Ca2+ from acidic stores. Biochem Soc Trans 34:922–926

    Article  PubMed  CAS  Google Scholar 

  19. Galione A, Churchill GC (2002) Interactions between calcium release pathways: multiple messengers and multiple stores. Cell Calcium 32:343–354

    Article  PubMed  CAS  Google Scholar 

  20. Galione A, Lee HC, Busa WB (1991) Ca2+-induced Ca2+ release in sea urchin egg homogenates: modulation by cyclic ADP-ribose. Science 253:1143–1146

    Article  PubMed  CAS  Google Scholar 

  21. Galione A, Petersen OH (2005) The NAADP receptor: new receptors or new regulation? Mol Interv 5:73–79

    Article  PubMed  CAS  Google Scholar 

  22. Gambara G, Billington RA, Debidda M, D’Alessio A, Palombi F, Ziparo E, Genazzani AA, Filippini A (2008) NAADP-induced Ca2+ signaling in response to endothelin is via the receptor subtype B and requires the integrity of lipid rafts/caveolae. J Cell Physiol 216:396–404

    Article  PubMed  CAS  Google Scholar 

  23. Genazzani AA, Galione A (1996) Nicotinic acid-adenine dinucleotide phosphate mobilizes Ca2+ from a thapsigargin-insensitive pool. Biochem J 315:721–725

    PubMed  CAS  Google Scholar 

  24. Genazzani AA, Galione A (1997) A Ca2+ release mechanism gated by the novel pyridine nucleotide, NAADP. Trends Pharmacol Sci 18:108–110

    Article  PubMed  CAS  Google Scholar 

  25. Genazzani AA, Mezna M, Dickey DM, Michelangeli F, Walseth TF, Galione A (1997) Pharmacological properties of the Ca2+-release mechanism sensitive to NAADP in the sea urchin egg. Br J Pharmacol 121:1489–1495

    Article  PubMed  CAS  Google Scholar 

  26. Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891–2906

    Article  PubMed  CAS  Google Scholar 

  27. Huang X, Godfrey TE, Gooding WE, McCarty KS Jr, Gollin SM (2006) Comprehensive genome and transcriptome analysis of the 11q13 amplicon in human oral cancer and synteny to the 7F5 amplicon in murine oral carcinoma. Genes Chromosomes Cancer 45:1058–1069

    Article  PubMed  CAS  Google Scholar 

  28. Ishibashi K, Suzuki M, Imai M (2000) Molecular cloning of a novel form (two-repeat) protein related to voltage-gated sodium and calcium channels. Biochem Biophys Res Commun 270:370–376

    Article  PubMed  CAS  Google Scholar 

  29. Kalay E, Caylan R, Kiroglu AF, Yasar T, Collin RW, Heister JG, Oostrik J, Cremers CW, Brunner HG, Karaguzel A, Kremer H (2007) A novel locus for autosomal recessive nonsyndromic hearing impairment, DFNB63, maps to chromosome 11q13.2–q13.4. J Mol Med 85:397–404

    Article  PubMed  CAS  Google Scholar 

  30. Kamphoven JH, de Ruiter MM, Winkel LP, Van den Hout HM, Bijman J, De Zeeuw CI, Hoeve HL, Van Zanten BA, Van der Ploeg AT, Reuser AJ (2004) Hearing loss in infantile Pompe’s disease and determination of underlying pathology in the knockout mouse. Neurobiol Dis 16:14–20

    Article  PubMed  Google Scholar 

  31. Khan SY, Riazuddin S, Tariq M, Anwar S, Shabbir MI, Riazuddin SA, Khan SN, Husnain T, Ahmed ZM, Friedman TB (2007) Autosomal recessive nonsyndromic deafness locus DFNB63 at chromosome 11q13.2–q13.3. Hum Genet 120:789–793

    Article  PubMed  CAS  Google Scholar 

  32. Kinnear NP, Boittin FX, Thomas JM, Galione A, Evans AM (2004) Lysosome–sarcoplasmic reticulum junctions. A trigger zone for calcium signaling by nicotinic acid adenine dinucleotide phosphate and endothelin-1. J Biol Chem 279:54319–54326

    Article  PubMed  CAS  Google Scholar 

  33. Kinnear NP, Wyatt CN, Clark JH, Calcraft PJ, Fleischer S, Jeyakumar LH, Nixon GF, Evans AM (2008) Lysosomes co-localize with ryanodine receptor subtype 3 to form a trigger zone for calcium signalling by NAADP in rat pulmonary arterial smooth muscle. Cell Calcium 44:190–201

    Article  PubMed  CAS  Google Scholar 

  34. Lee HC (2005) Nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium signaling. J Biol Chem 280:33693–33696

    Article  PubMed  CAS  Google Scholar 

  35. Lee HC, Aarhus R (1995) A derivative of NADP mobilizes calcium stores insensitive to inositol trisphosphate and cyclic ADP-ribose. J Biol Chem 270:2152–2157

    Article  PubMed  CAS  Google Scholar 

  36. Lee HC, Aarhus R (2000) Functional visualization of the separate but interacting calcium stores sensitive to NAADP and cyclic ADP-ribose. J Cell Sci 113:4413–4420

    PubMed  CAS  Google Scholar 

  37. Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, Churchill GC, Schuchman EH, Galione A, Platt FM (2008) Niemann–Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med 14:1247–1255

    Article  PubMed  CAS  Google Scholar 

  38. Lopez JJ, Redondo PC, Salido GM, Pariente JA, Rosado JA (2006) Two distinct Ca2+ compartments show differential sensitivity to thrombin, ADP and vasopressin in human platelets. Cell Signal 18:373–381

    Article  PubMed  CAS  Google Scholar 

  39. Macgregor A, Yamasaki M, Rakovic S, Sanders L, Parkesh R, Churchill GC, Galione A, Terrar DA (2007) NAADP controls cross-talk between distinct Ca2+ stores in the heart. J Biol Chem 282:15302–15311

    Article  PubMed  CAS  Google Scholar 

  40. Masgrau R, Churchill GC, Morgan AJ, Ashcroft SJ, Galione A (2003) NAADP, a new second messenger for glucose-induced Ca2+ responses in clonal pancreatic beta cells. Curr Biol 13:247–251

    Article  PubMed  CAS  Google Scholar 

  41. Menteyne A, Burdakov A, Charpentier G, Petersen OH, Cancela JM (2006) Generation of specific Ca2+ signals from Ca2+ stores and endocytosis by differential coupling to messengers. Curr Biol 16:1931–1937

    Article  PubMed  CAS  Google Scholar 

  42. Moccia F, Lim D, Kyozuka K, Santella L (2004) NAADP triggers the fertilization potential in starfish oocytes. Cell Calcium 36:515–524

    Article  PubMed  CAS  Google Scholar 

  43. Morgan AJ, Galione A (2007) NAADP induces pH changes in the lumen of acidic Ca2+ stores. Biochem J 402:301–310

    Article  PubMed  CAS  Google Scholar 

  44. Morgan AJ, Galione A (2008) Investigating cADPR and NAADP in intact and broken cell preparations. Methods 46:194–203

    Article  PubMed  CAS  Google Scholar 

  45. Naylor E, Arredouani A, Vasudevan SR, Lewis AM, Parkesh R, Mizote A, Rosen D, Thomas JM, Izumi M, Ganesan A, Galione A, Churchill GC (2009) Identification of a chemical probe for NAADP by virtual screening. Nat Chem Biol 5:220–226

    Article  PubMed  CAS  Google Scholar 

  46. Peiter E, Maathuis FJ, Mills LN, Knight H, Pelloux J, Hetherington AM, Sanders D (2005) The vacuolar Ca2+-activated channel TPC1 regulates germination and stomatal movement. Nature 434:404–408

    Article  PubMed  CAS  Google Scholar 

  47. Piper RC, Luzio JP (2004) CUPpling calcium to lysosomal biogenesis. Trends Cell Biol 14:471–473

    Article  PubMed  CAS  Google Scholar 

  48. Pryor PR, Mullock BM, Bright NA, Gray SR, Luzio JP (2000) The role of intraorganellar Ca2+ in late endosome–lysosome heterotypic fusion and in the reformation of lysosomes from hybrid organelles. J Cell Biol 149:1053–1062

    Article  PubMed  CAS  Google Scholar 

  49. Pryor PR, Reimann F, Gribble FM, Luzio JP (2006) Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic. Traffic 7:1388–1398

    Article  PubMed  CAS  Google Scholar 

  50. Soyombo AA, Tjon-Kon-Sang S, Rbaibi Y, Bashllari E, Bisceglia J, Muallem S, Kiselyov K (2006) TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. J Biol Chem 281:7294–7301

    Article  PubMed  CAS  Google Scholar 

  51. Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Jakobsdottir M, Steinberg S, Gudjonsson SA, Palsson A, Thorleifsson G, Palsson S, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Vermeulen SH, Goldstein AM, Tucker MA, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K (2008) Two newly identified genetic determinants of pigmentation in Europeans. Nat Genet 40:835–837

    Article  PubMed  CAS  Google Scholar 

  52. Yamasaki M, Masgrau R, Morgan AJ, Churchill GC, Patel S, Ashcroft SJ, Galione A (2004) Organelle selection determines agonist-specific Ca2+ signals in pancreatic acinar and beta cells. J Biol Chem 279:7234–7240

    Article  PubMed  CAS  Google Scholar 

  53. Yamasaki M, Thomas JM, Churchill GC, Garnham C, Lewis AM, Cancela JM, Patel S, Galione A (2005) Role of NAADP and cADPR in the induction and maintenance of agonist-evoked Ca2+ spiking in mouse pancreatic acinar cells. Curr Biol 15:874–878

    Article  PubMed  CAS  Google Scholar 

  54. Yu FH, Yarov-Yarovoy V, Gutman GA, Catterall WA (2005) Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol Rev 57:387–395

    Article  PubMed  CAS  Google Scholar 

  55. Zhang F, Jin S, Yi F, Li PL (2008) TRP-ML1 functions as a lysosomal NAADP-sensitive Ca2+ release channel in coronary arterial myocytes. J Cell Mol Med doi:10.1111/j.1582-4934.2008.00486.x

  56. Zhang F, Li PL (2007) Reconstitution and characterization of a nicotinic acid adenine dinucleotide phosphate (NAADP)-sensitive Ca2+ release channel from liver lysosomes of rats. J Biol Chem 282:25259–25269

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank American Heart Association, British Heart Foundation, US National Institutes of Health, and the Wellcome Trust for financial support of their research.

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Authors and Affiliations

  1. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK

    Antony Galione, John Parrington, Abdelilah Arredouani & Xiaotong Cheng

  2. Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland, UK

    A. Mark Evans

  3. Department of Physiology and Biophysics, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ, USA

    Jianjie Ma

  4. Department of Neuroscience, Biochemistry and Center for Molecular Neurobiology, The Ohio State University, Columbus, OH, USA

    Michael X. Zhu

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  1. Antony Galione
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  2. A. Mark Evans
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  3. Jianjie Ma
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  4. John Parrington
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  5. Abdelilah Arredouani
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  6. Xiaotong Cheng
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  7. Michael X. Zhu
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Correspondence to Antony Galione or Michael X. Zhu.

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Galione, A., Evans, A.M., Ma, J. et al. The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca2+ release channels. Pflugers Arch - Eur J Physiol 458, 869–876 (2009). https://doi.org/10.1007/s00424-009-0682-y

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  • DOI: https://doi.org/10.1007/s00424-009-0682-y

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