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Effect of a temperature increase in the non-noxious range on proton-evoked ASIC and TRPV1 activity

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Abstract

Acid-sensing ion channels (ASICs) are neuronal H+-gated cation channels, and the transient receptor potential vanilloid 1 channel (TRPV1) is a multimodal cation channel activated by low pH, noxious heat, capsaicin, and voltage. ASICs and TRPV1 are present in sensory neurons. It has been shown that raising the temperature increases TRPV1 and decreases ASIC H+-gated current amplitudes. To understand the underlying mechanisms, we have analyzed ASIC and TRPV1 function in a recombinant expression system and in dorsal root ganglion (DRG) neurons at room and physiological temperature. We show that temperature in the range studied does not affect the pH dependence of ASIC and TRPV1 activation. A temperature increase induces, however, a small alkaline shift of the pH dependence of steady-state inactivation of ASIC1a, ASIC1b, and ASIC2a. The decrease in ASIC peak current amplitudes at higher temperatures is likely in part due to the observed accelerated open channel inactivation kinetics and for some ASIC types to the changed pH dependence of steady-state inactivation. The increase in H+-activated TRPV1 current at the higher temperature is at least in part due to a hyperpolarizing shift in its voltage dependence. The contribution of TRPV1 relative to ASICs to H+-gated currents in DRG neurons increases with higher temperature and acidity. Still, ASICs remain the principal pH sensors of DRG neurons at 35°C in the pH range ≥6.

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Abbreviations

AP:

Action potential

ASIC:

Acid-sensing ion channel

BCTC:

4-(3-Chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide

CHO:

Chinese hamster ovary

DRG:

Dorsal root ganglia

ENaC:

Epithelial sodium channel

HEK:

Human embryonic kidney

nH :

Hill number

pH0.5 :

pH of half-maximal activation

pHIn0.5 :

pH of half-maximal inactivation

SSIN:

Steady-state inactivation

τ I :

Time constant of open channel inactivation

τ R :

Time constant of recovery from inactivation

TRPV1:

Transient receptor potential vanilloid 1

V 0.5 :

Voltage of half-maximal conductance

V m :

Membrane potential

References

  1. Askwith CC, Benson CJ, Welsh MJ, Snyder PM (2001) DEG/ENaC ion channels involved in sensory transduction are modulated by cold temperature. Proc Natl Acad Sci USA 98:6459–6463

    Article  CAS  PubMed  Google Scholar 

  2. Benson CJ, Xie JH, Wemmie JA, Price MP, Henss JM, Welsh MJ, Snyder PM (2002) Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons. Proc Natl Acad Sci USA 99:2338–2343

    Article  CAS  PubMed  Google Scholar 

  3. Bianchi BR, Lee CH, Jarvis MF, El Kouhen R, Moreland RB, Faltynek CR, Puttfarcken PS (2006) Modulation of human TRPV1 receptor activity by extracellular protons and host cell expression system. Eur J Pharmacol 537:20–30

    Article  CAS  PubMed  Google Scholar 

  4. Blair NT, Bean BP (2002) Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J Neurosci 22:10277–10290

    CAS  PubMed  Google Scholar 

  5. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313

    Article  CAS  PubMed  Google Scholar 

  6. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor—a heat-activated ion channel in the pain pathway. Nature 389:816–824

    Article  CAS  PubMed  Google Scholar 

  7. Chen C-C, Zimmer A, Sun W-H, Hall J, Brownstein MJ, Zimmer A (2002) A role for ASIC3 in the modulation of high-intensity pain stimuli. PNAS 99:8992–8997

    CAS  PubMed  Google Scholar 

  8. Chen X, Paukert M, Kadurin I, Pusch M, Grunder S (2006) Strong modulation by RFamide neuropeptides of the ASIC1b/3 heteromer in competition with extracellular calcium. Neuropharmacology 50:964–974

    Article  CAS  PubMed  Google Scholar 

  9. Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–187

    Article  CAS  PubMed  Google Scholar 

  10. Deval E, Baron A, Lingueglia E, Mazarguil H, Zajac JM, Lazdunski M (2003) Effects of neuropeptide SF and related peptides on acid sensing ion channel 3 and sensory neuron excitability. Neuropharmacol 44:662–671

    Article  CAS  Google Scholar 

  11. Donier E, Rugiero F, Jacob C, Wood JN (2008) Regulation of ASIC activity by ASIC4—new insights into ASIC channel function revealed by a yeast two-hybrid assay. Eur J Neurosci 28:74–86

    Article  PubMed  Google Scholar 

  12. East CE, Begg L, Henshall NE, Marchant P, Wallace K (2007) Local cooling for relieving pain from perineal trauma sustained during childbirth. Cochrane Database Syst Rev: CD006304

  13. Escoubas P, DeWeille JR, Lecoq A, Diochot S, Waldmann R, Champigny G, Moinier D, Ménez A, Lazdunski M (2000) Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J Biol Chem 275:25116–25121

    Article  CAS  PubMed  Google Scholar 

  14. Gonzales EB, Kawate T, Gouaux E (2009) Pore architecture and ion sites in acid-sensing ion channels and P2X receptors. Nature 460:599–604

    Article  CAS  PubMed  Google Scholar 

  15. Good NE, Winget GD, Winter W, Connolly TN, Izawa S, Singh RM (1966) Hydrogen ion buffers for biological research. Biochemistry 5:467–477

    Article  CAS  PubMed  Google Scholar 

  16. Hesselager M, Timmermann DB, Ahring PK (2004) pH dependency and desensitization kinetics of heterologously expressed combinations of acid-sensing ion channel subunits. J Biol Chem 279:11006–11015

    Article  CAS  PubMed  Google Scholar 

  17. Hille B (2001) Ion channels of excitable membranes. Sinauer Associates, Sunderland

    Google Scholar 

  18. Holzer P (2009) Acid-sensitive ion channels and receptors. Handb Exp Pharmacol 194:283–332

    Article  CAS  PubMed  Google Scholar 

  19. Horisberger JD, Chraibi A (2004) Epithelial sodium channel: a ligand-gated channel? Nephron Physiol 96:p37–p41

    Article  CAS  PubMed  Google Scholar 

  20. Jasti J, Furukawa H, Gonzales EB, Gouaux E (2007) Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature 449:316–323

    Article  CAS  PubMed  Google Scholar 

  21. Jones NG, Slater R, Cadiou H, McNaughton P, McMahon SB (2004) Acid-induced pain and its modulation in humans. J Neurosci 24:10974–10979

    Article  CAS  PubMed  Google Scholar 

  22. Jordt SE, Tominaga M, Julius D (2000) Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci USA 97:8134–8139

    Article  CAS  PubMed  Google Scholar 

  23. Koplas PA, Rosenberg RL, Oxford GS (1997) The role of calcium in the desensitization of capsaicin responses in rat dorsal root ganglion neurons. J Neurosci 17:3525–3537

    CAS  PubMed  Google Scholar 

  24. Krishtal O (2003) The ASICs: signaling molecules? Modulators? Trends Neurosci 26:477–483

    Article  CAS  PubMed  Google Scholar 

  25. Latorre R, Brauchi S, Orta G, Zaelzer C, Vargas G (2007) ThermoTRP channels as modular proteins with allosteric gating. Cell Calcium 42:427–438

    Article  CAS  PubMed  Google Scholar 

  26. Lawson SN, Perry MJ, Prabhakar E, McCarthy PW (1993) Primary sensory neurones: neurofilament, neuropeptides, and conduction velocity. Brain Res Bull 30:239–243

    Article  CAS  PubMed  Google Scholar 

  27. Lingueglia E, de Weille JR, Bassilana F, Heurteaux C, Sakai H, Waldmann R, Lazdunski M (1997) A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J Biol Chem 272:29778–29783

    Article  CAS  PubMed  Google Scholar 

  28. Matta JA, Ahern GP (2007) Voltage is a partial activator of rat thermosensitive TRP channels. J Physiol 585:469–482

    Article  CAS  PubMed  Google Scholar 

  29. Mogil JS, Breese NM, Witty M-F, Ritchie J, Rainville M-L, Ase A, Abbadi N, Stucky CL, Seguela P (2005) Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli. J Neurosci 25:9893–9901

    Article  CAS  PubMed  Google Scholar 

  30. Mohan C (2003) Calbiochem buffer guide. EMD Biosciences, Darmstadt

    Google Scholar 

  31. Neelands TR, Jarvis MF, Han P, Faltynek CR, Surowy CS (2005) Acidification of rat TRPV1 alters the kinetics of capsaicin responses. Mol Pain 1:28

    Article  PubMed  Google Scholar 

  32. Neelands TR, Zhang XF, McDonald H, Puttfarcken P (2010) Differential effects of temperature on acid-activated currents mediated by TRPV1 and ASIC channels in rat dorsal root ganglion neurons. Brain Res 1329:55–66

    Article  CAS  PubMed  Google Scholar 

  33. Ni D, Lee LY (2008) Effect of increasing temperature on TRPV1-mediated responses in isolated rat pulmonary sensory neurons. Am J Physiol Lung Cell Mol Physiol 294:L563–L571

    Article  CAS  PubMed  Google Scholar 

  34. Petruska JC, Napaporn J, Johnson RD, Gu JGG, Cooper BY (2000) Subclassified acutely dissociated cells of rat DRG: histochemistry and patterns of capsaicin-, proton-, and ATP-activated currents. J Neurophysiol 84:2365–2379

    CAS  PubMed  Google Scholar 

  35. Poirot O, Berta T, Decosterd I, Kellenberger S (2006) Distinct ASIC currents are expressed in rat putative nociceptors and are modulated by nerve injury. J Physiol 576:215–234

    Article  CAS  PubMed  Google Scholar 

  36. Poirot O, Vukicevic M, Boesch A, Kellenberger S (2004) Selective regulation of acid-sensing ion channel 1 by serine proteases. J Biol Chem 279:38448–38457

    Article  CAS  PubMed  Google Scholar 

  37. Price MP, McIlwrath SL, Xie JH, Cheng C, Qiao J, Tarr DE, Sluka KA, Brennan TJ, Lewin GR, Welsh MJ (2001) The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32:1071–1083

    Article  CAS  PubMed  Google Scholar 

  38. Sluka KA, Price MP, Breese NA, Stucky CL, Wemmie JA, Welsh MJ (2003) Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain 106:229–239

    Article  CAS  PubMed  Google Scholar 

  39. Stucky CL, Dubin AE, Jeske NA, Malin SA, McKemy DD, Story GM (2009) Roles of transient receptor potential channels in pain. Brain Res Rev 60:2–23

    Article  CAS  PubMed  Google Scholar 

  40. Sutherland SP, Benson CJ, Adelman JP, McCleskey EW (2001) Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Sci USA 98:711–716

    Article  CAS  PubMed  Google Scholar 

  41. Szallasi A, Cortright DN, Blum CA, Eid SR (2007) The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6:357–372

    Article  CAS  PubMed  Google Scholar 

  42. Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543

    Article  CAS  PubMed  Google Scholar 

  43. Tominaga M, Wada M, Masu M (2001) Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc Natl Acad Sci USA 98:6951–6956

    Article  CAS  PubMed  Google Scholar 

  44. Ugawa S, Ueda T, Ishida Y, Nishigaki M, Shibata Y, Shimada S (2002) Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. J Clin Invest 110:1185–1190

    CAS  PubMed  Google Scholar 

  45. Valenzano KJ, Grant ER, Wu G, Hachicha M, Schmid L, Tafesse L, Sun Q, Rotshteyn Y, Francis J, Limberis J, Malik S, Whittemore ER, Hodges D (2003) N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I. In vitro characterization and pharmacokinetic properties. J Pharmacol Exp Ther 306:377–386

    Article  CAS  PubMed  Google Scholar 

  46. Vellani V, Mapplebeck S, Moriondo A, Davis JB, McNaughton PA (2001) Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide. J Physiol 534:813–825

    Article  CAS  PubMed  Google Scholar 

  47. Vlachova V, Lyfenko A, Orkand RK, Vyklicky L (2001) The effects of capsaicin and acidity on currents generated by noxious heat in cultured neonatal rat dorsal root ganglion neurones. J Physiol 533:717–728

    Article  CAS  PubMed  Google Scholar 

  48. Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B (2004) The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430:748–754

    Article  CAS  PubMed  Google Scholar 

  49. Vukicevic M, Weder G, Boillat A, Boesch A, Kellenberger S (2006) Trypsin cleaves acid-sensing ion channel 1a in a domain that is critical for channel gating. J Biol Chem 281:714–722

    Article  CAS  PubMed  Google Scholar 

  50. Vyklicky L, Vlachova V, Vitaskova Z, Dittert I, Kabat M, Orkand RK (1999) Temperature coefficient of membrane currents induced by noxious heat in sensory neurones in the rat. J Physiol 517(Pt 1):181–192

    Article  CAS  PubMed  Google Scholar 

  51. Waldmann R, Bassilana F, de Weille J, Champigny G, Heurteaux C, Lazdunski M (1997) Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons. J Biol Chem 272:20975–20978

    Article  CAS  PubMed  Google Scholar 

  52. Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M (1997) A proton-gated cation channel involved in acid-sensing. Nature 386:173–177

    Article  CAS  PubMed  Google Scholar 

  53. Wang WZ, Chu XP, Li MH, Seeds J, Simon RP, Xiong ZG (2006) Modulation of acid-sensing ion channel currents, acid-induced increase of intracellular Ca2+, and acidosis-mediated neuronal injury by intracellular pH. J Biol Chem 281:29369–29378

    Article  CAS  PubMed  Google Scholar 

  54. Wemmie JA, Price MP, Welsh MJ (2006) Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci 29:578–586

    Article  CAS  PubMed  Google Scholar 

  55. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Laurent Schild, Aurélien Boillat, Benoîte Bargeton, Cedric Laedermann, Olivier Poirot, and Miguel van Bemmelen for their comments on a previous version of the manuscript and for many discussions. This research was supported by grant 31003A0-117717 of the Swiss National Science Foundation to S.K.

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The authors declare that they have no conflict of interest.

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Correspondence to Stephan Kellenberger.

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Blanchard, M.G., Kellenberger, S. Effect of a temperature increase in the non-noxious range on proton-evoked ASIC and TRPV1 activity. Pflugers Arch - Eur J Physiol 461, 123–139 (2011). https://doi.org/10.1007/s00424-010-0884-3

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