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Roles of ASICs in Nociception and Proprioception

  • Cheng-Han Lee
  • Chih-Cheng Chen
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1099)

Abstract

Acid-sensing ion channels (ASICs) are a group of proton-gated ion channels belonging to the degenerin/epithelial sodium channel (DED/ENaC) family. There are at least six ASIC subtypes – ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4 – all expressed in somatosensory neurons. ASIC3 is the most abundant in dorsal root ganglia (DRG) and the most sensitive to extracellular acidification. ASICs were found as the major player involved in acid-induced pain in humans. Accumulating evidence has further shown ASIC3 as the molecular determinant involved in pain-associated tissue acidosis in rodent models. Besides having a role in nociception, members of the DEG/ENaC family have been demonstrated as essential mechanotransducers in the nematode Caenorhabditis elegans and fly Drosophila melanogaster. ASICs are mammalian homologues of DEG/ENaC and therefore may play a role in mechanotransduction. However, the role of ASICs in neurosensory mechanotransduction is disputed. Here we review recent studies to probe the roles of ASICs in acid nociception and neurosensory mechanotransduction. In reviewing genetic models and delicate electrophysiology approaches, we show ASIC3 as a dual-function protein for both acid-sensing and mechano-sensing in somatosensory nerves and therefore involved in regulating both nociception and proprioception.

Keywords

ASIC3 DRG Mechanotransduction Pain 

Notes

Acknowledgments

This work was supported by intramural funding of Academia Sinica and grants from the Ministry of Science and Technology of Taiwan (MOST 105-2320-B-001-018-MY3, MOST 106-2319-B-001-004, and MOST 107-2321-B-001-020).

References

  1. 1.
    Birdsong WT, Fierro L, Willians FG, Spelta V, Naves LA, Knowles M, Marsh-Haffner J, Adelman JP, Almers W, Elde RP, McCleskey EW (2010) Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels. Neuron 68:739–749CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Borzan J, Zhao C, Meyer RA, Raja SN (2010) A role for acid-sensing ion channel 3, but not acid-sensing ion channel 2, in sensing dynamic mechanical stimuli. Anesthesiology 113:647–654PubMedPubMedCentralGoogle Scholar
  3. 3.
    Calleji G, Castellanos A, Castany M, Gual A, Luna C, Acosta MC, Galar J, Giblin JP, Gasull X (2015) Acid-sensing ion channels detect moderate acidifications to induce ocular pain. Pain 156:483–495CrossRefGoogle Scholar
  4. 4.
    Chalfie M (2009) Neurosensory mechanotransduction. Nat Rev Mol Cell Biol 10:44–52CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chen CC, Zimmer A, Sun WH, Hall J, Browstein MJ, Zimmer A (2002) A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc Natl Acad Sci U S A 99:8992–8997CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chen CC, Wong CW (2013) Neurosensory mechanotransduction through acid-sensing ion channels. J Cell Mol Med 17:337–349CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chen WN, Lee CH, Lin SH, Wong CW, Sun WH, Wood JN, Chen CC (2014) Roles of AISC3, TRPV1, and Nav1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Mol Pain 10:40CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cheng CF, Chen IL, Cheng MH, Lian WS, Lin CC, Kuo TBJ, Chen CC (2011) Acid-sensing ion channel 3, but not capsaicin receptor TRPV1, plays a protective role in isoproterenol-induced myocardial ischemic in mice. Circ J 75:174–178CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cheng CM, Lin YW, Bellin RM, Steward RL Jr, Cheng YR, PR LD, Chen CC (2010) Probing localized neural mechanotransduction through surface-modified elastomeric matrices and electrophysiology. Nat Protoc 5:714–724CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330:55–60CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    De la Roche J, Walther I, Leonow W, Hage A, Eberhardt M, Fisher M, Reeh PW, Sauer S, Leffler A (2016) Lactate is a potent inhibitor of the capsaicin receptor TRPV1. Sci Rep 6:36740CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Deval E, Noel J, Lay N, Alloui A, Dichot S, Friend V, Jodar M, Lazdunski M, Lingueglia E (2008) ASIC3, a senor of acidic and primary inflamatory pain. EMBO J 27:3047–3055CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Deval E, Gasuall X, Noel J, Salinas M, Baron A, Diochot S, Lingueglia E (2010) Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther 128:549–558CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Deval E, Noel J, Gasull X, Delaunay A, Alloui A, Friend V, Eschalier A, Lazdunski M, Lingueglia E (2011) Acid-sensing ion channels in postoperative pain. J Neurosci 31:6059–6066CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Diochot S, Alloui A, Rodrigues P, Dauvois M, Friend V, Aissouni Y, Eschalier A, Lingueglia E, Baron A (2016) Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain. Pain 157:552–559CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Diochot S, Baron A, Rash LD, Deval E, Escoubas P, Scarzello S, Salinas M, Lazdunski M (2004) A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J 23:1516–1525CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Diochot S, Baron A, Salinas M, Douguet D, Scarzello S, Dabert-Gay AS, Debayle D, Friend V, Alloui A, Lazdunski M, Lingueglia E (2012) Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature 490:552–555CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Drew LJ, Rohrer DK, Price MP, Blaver KE, Cockayne DA, Cesare P, Wood JN (2004) Acid-sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurones. J Physiol 556:691–710CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Du J, Reznikov LR, Price MP, Zha XM, Lu Y, TO M, Wemmie JA, Welsh MJ (2014) Proton are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala. Proc Natl Acad Sci U S A 111:8961–8966CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fromy B, Lingueglia E, Sigaudo-Roussel D, Saumet JL, Lazdunski M (2012) Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers. Nat Med 18:1205–1207CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Gao M, Long H, Ma W, Liao L, Yang X, Zhou Y, Shan D, Huang R, Jian F, Wang Y, Lai W (2016) The role of periodontal ASIC3 in orofacial pain induced by experimental tooth movement in rats. Eur J Orthod 38:577–583CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gautam M, Benson CJ, Ranier JD, Light AR, SLuka KA (2012) ASICs do not play a role in maintaining hyperalgesia induced by repeated intramuscular acid injections. Pain Res Treat 2012:817347PubMedPubMedCentralGoogle Scholar
  23. 23.
    Gong WY, Abdelhamid RE, Carvalho CS, Sluka KA (2016) Resident macrophages in muscle contribute to development of hyperalgesia in a mouse model of noninflammatory muscle pain. J Pain 17:1081–1094CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Gregory NS, Brito RG, Fusaro MC, Sluka KA (2016) ASIC3 is required for development of fatigue-induced hyperalgesia. Mol Neurobiol 53:1020–1030CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hao J, Delmas P (2011) Recording of mechanosensitive currents using piezoelectrically driven mechanostimulator. Nat Protoc 6:979–990CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hattori T, Chen J, Harding AM, Price MP, Lu Y, Abbound FM, Benson CJ (2009) ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglion neurons. Circ Res 105:279–286CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hiasa M, Okui T, Allette YM, Ripsch MS, Sun-Wada GH, Wakabayashi H, Roodman GD, White FA, Yoneda T (2017) Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3. Cancer Res 77:1283–1295CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hong GS, Lee B, Wee J, Chun H, Kim H, Jung J, Cha JY, Riew TR, Kim GH, Kim IB, Oh U (2016) Tentonin 3/TMEM150c confers distinct mechanosensitive currents in dorsal-root ganglion neurons with proprioceptive function. Neuron 91:107–118CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hsieh WS, Kung CC, Huang SL, Lin SC, Sun WH (2017) TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis. Sci Rep 7:8870CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ikeuchi M, Kolker SJ, Bumes LA, Walder RY, Sluka KA (2008) Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation. Pain 137:662–669CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Immke DC, McCleskey EW (2001) Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci 4:869–870CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Issberner U, Reeh PW, Steen KH (1996) Pain due to tissue acidosis: a mechanism for inflammatory and ischemic myalgia? Neurosci Lett 208:191–194CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Izumi M, Ikeuchi M, Ji Q, Tani T (2012) Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis. J Biomed Sci 19:77CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Jones NG, Slater R, Cadiou H, McNaughton P, McMahon SB (2004) Acid-induced pain and its modulation in humans. J Neurosci 24:10974–10979CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kang S, Jang JH, Price MP, Gautam M, Benson CJ, Gong H, Welsh MJ, Brennan TJ (2012) Simultaneous disruption of mouse ASIC1a, ASIC2, and ASIC3 genes enhances cutaneous mechanosensitivity. PLoS One 7:e35225CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kobayashi Y, Sekiguchi M, Konno SI (2017) Effect of acid-sensing ion channels inhibitors on pain-related behavior by nucleus pulposus applied on the nerve root in rats. Spine 42:E633–E641CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lee CH, Sun WH, Lin SH, Chen CC (2011) Role of the acid-sensing ion channel 3 in blood volume control. Circ J 75:874–883CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lee JYP, Saez NJ, Christofori-Armstrong B, Anangi R, King GF, Smith MT, Rash LD (2017) Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain. Br J Pharmacol. 10.1111.bjp.14089Google Scholar
  39. 39.
    Lin SH, Cheng YR, Banks RW, Min MY, Bewick GS, Chen CC (2016) Evidence for the involvement of ASIC3 in sensory mechanotransduction in proprioceptors. Nat Commun 7:11460CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lin SH, Sun WH, Chen CC (2015) Genetic exploration of the role of acid-sensing ion channels. Neuropharmacology 94:99–118CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Lin YW, Cheng CM, LeDuc PR, Chen CC (2009) Understanding sensory nerve mechanotransduction through localized elastomeric matrix control. PLoS One 4:e4293CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Molliver DC, Immke DC, Fiero L, Pare M, Rice FL, McCleskey EW (2005) ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons. Mol Pain 1:35CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nilius B, Honore E (2012) Sensing pressure with ion channels. Trends Neurosci 35:477–486CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Omerbasic D, Schuhmacher LN, Bernal Sierra YA, Smith ES, Lewin GR (2015) ASICs and mammalian mechanoreceptor function. Neuropharmacology 94:80–86CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Page AJ, Brierley SM, Martin CM, Price MP, Symonds E, Butler R, Wemmie JA, Blackshaw LA (2005) Differential contribution of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function. Gut 54:1408–1415CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Pan HL, Longhurst JC, Eisenach JC, Chen SR (1999) Role of protons in activation of cardiac sympathetic C-fiber afferents during ischemia in cats. J Physiol 518:857–866CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Price MP, McIlwrath SL, Xie J, 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 32:1071–1083CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Price MP, Lewin GR, McIlwrath SL, Cheng C, Xie J, Heppenstall PA, Stucky CL, Mannsfeldt AG, Brennan TJ, Drummond HA, Qiao J, Benson CJ, Tarr DE, Hrstka RF, Yang B, Williamson RA, Welsh MJ (2000) The mammalian sodium channel BNC1 is required for normal touch sensation. Nature 407:1007–1011CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ranade SS, Syeda R, Patapoutian A (2015) Mechanically activated ion channels. Neuron 87:1162–1179CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Reimers S, Lee CH, Kalbacher H, Tian Y, Hung CH, Schmidt A, Prokop L, Kauferstein S, Mebs D, Chen CC, Grunder S (2017) Identification of a cono-RFamide from the venom of Conus textile that targets ASIC3 and enhances muscle pain. Proc Natl Acad Sci U S A 114:E3507–E3515CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ross JL, Queme LF, Cohen ER, Green KJ, Lu P, Shank AT, An S, Hudgins RC, Jankowski MP (2016) Muscle IL1β drives ischemic myalgia via ASIC3-mediated sensory neuron sensitization. J Neurosci 36:6857–6871CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Schmitz JPJ, van Dijk JP, Hilbers PJ, Nicolay K, Jeneson JL, Stegeman DF (2012) Unchanges muscle fiber conduction velocity relates to mild acidosis during exhaustive bicycling. Eur J Appl Physiol 112:1593–1602CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Schwartz MG, Namer B, Reeh PW, Fischer MJM (2017) TRPA1 and TRPV1 antagonists do not inhibit human acidosis-induced pain. J Pain 18:526–534CrossRefGoogle Scholar
  54. 54.
    Sluka KA, Price MP, Breese NM, 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 106:229–239CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Sluka KA, Radhakrishnan R, Benson CJ, Eshcol JO, Price MP, Babiski K, Audette KM, Audette KM, Yeomans DC, Wilson SP (2007) ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain 129:102–112CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Sugimura N, Ikeuchi M, Izumi M, Kawano T, Aso K, Kato T, Ushida T, Yokoyama M, Tani T (2015) Repeated intra-articular injections of acidic saline produce long-lasting joint pain and widespread hyperalgesia. Eur J Pain 19:629–638CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Su YS, Mei HR, Wang CH, Sun WH (2018) Peripheral 5HT3 mediates mirror-image pain by a cross-talk with acid-sensing ion channel 3. Neuropharmacology 130:92–104CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Sun WH, Chen CC (2016) Roles of proton-sensing receptors in the transition from acute to chronic pain. J Dent Res 95:135–142CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    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 110:1185–1190CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Walder RY, Rasmussen LA, Rainier JD, Light AR, Wemmie JA, Sluka KA (2010) ASIC1 and ASIC3 play different roles in the development of hyperalgesia after inflammatory muscle injury. J Pain 11:210–218CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Waldmann R, Champigny G, Bassliana F, Heurteaux C, Lazdunski M (1997) A proton-gated cation channel involved in acid-sensing. Nature 386:173–177CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Wemmie JA, Taugher RJ, Kreple CJ (2013) Acid-sensing ion channels in pain and disease. Nat Rev Neurosci 14:461–471CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Wike-Hooley JL, Haveman J, Reinhold HS (1984) Thr relevance of tumor pH to the treatment of malignant disease. Radiother Oncol J Eur Soc Ther Radiol Oncol 2:343–366CrossRefGoogle Scholar
  64. 64.
    Woo SH, Lukacs V, de Nooij JC, Zaytseva D, Criddle CR, Francisco A, Jessell TM, Winkinson KA, Patapoutian A (2015) Piezo2 is the principle mechanotransduction channels for proprioception. Nat Neurosci 18:1756–1762CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Wu WL, Cheng CF, Sun WH, Wong CW, Chen CC (2012) Targeting ASIC3 for pain, anxiety, and insulin resistance. Pharmacol Ther 134:127–138CrossRefGoogle Scholar
  66. 66.
    Wu WL, Wang CH, Huang EY, Chen CC (2009) Asic3(−/−) female mice with hearing deficit affects social development of pups. PLoS One 4:e6508CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Xu XX, Cao Y, Ding TT, Fu KY, Li Y, Xie QF (2015) Role of TRPV1 and ASIC3 channels in experimental occlusal interference-induced hyperalgesia in rat masseter muscle. Eur J Pain 20:552–563CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Yan J, Edelmayer RM, Wei X, De Felice M, Porreca F, Dussor G (2011) Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache. Pain 152:106–113CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Yan J, Wei X, Bischoff C, Edelmayer RM, Dussor G (2013) pH-evoked dural afferent signaling is mediated by ASIC3 and is sensitized by mast cell mediators. Headache 53:1250–1262CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Yen YT, Tu PH, Chen CJ, Lin YW, Hsieh ST, Chen CC (2009) Role of acid-sensing ion channel 3 in subacute-phase inflammation. Mol Pain 5:1CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Zhang ZG, Zhang XL, Wang XY, Luo ZR, Song JC (2015) Inhibition of acid sensing ion channel by ligustrazine on angina model in rat. Am J Transl Res 7:1798–1811PubMedPubMedCentralGoogle Scholar
  72. 72.
    Zhong L, Hwang RY, Tracey WD (2010) Pickpocket is a DEG/ENaC protein required for mechanical nociception in Drosophila larvae. Curr Biol 20:429–434CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Zhu H, Ding J, Wu J, Liu T, Liang J, Tang Q, Jiao M (2017) Resveratrol attenuates bone cancer pain through regulating the expression levels of ASIC3 and activating cell autophagy. Acta Biochim Biophys Sin 49:1008–1014CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Institute of Biomedical Sciences, Academia SinicaTaipeiTaiwan
  2. 2.Taiwan Mouse Clinic – National Comprehensive Mouse Phenotyping and Drug Testing CenterTaipeiTaiwan

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