Acid-sensing ion channels in pain and disease

Key Points

  • Acid-sensing ion channels (ASICs) are permeable to Na+ (and other cations), activated by low extracellular pH and widely expressed in the CNS and the peripheral nervous system (PNS). ASICs are formed by homo- and heterotrimeric assemblies of subunits including ASIC1A, ASIC1B, ASIC2A, ASIC2B and ASIC3.

  • In the PNS, potential roles for ASICs in nociception and mechansensation have been investigated.

  • In the CNS, the ASIC1A subunit is largely required for acid-evoked currents and has been implicated in synaptic plasticity, mouse models of behaviour, neurodegenerative diseases, cancer and seizures.

  • ASICs are modulated by an increasing number of endogenous and exogenous compounds, including venoms from a tarantula, sea anemone and at least two snake species.

  • A few genetic studies have linked ASICs to human illnesses, but these associations need further confirmation.

  • ASICs are inhibited by amiloride at concentrations in the micromolar range. Amiloride has been used safely in humans as a diuretic and antihypertensive, and several small studies suggest that it might inhibit ASICs in humans to reduce pain, multiple sclerosis and migraine headache.


Why do neurons sense extracellular acid? In large part, this question has driven increasing investigation on acid-sensing ion channels (ASICs) in the CNS and the peripheral nervous system for the past two decades. Significant progress has been made in understanding the structure and function of ASICs at the molecular level. Studies aimed at clarifying their physiological importance have suggested roles for ASICs in pain, neurological and psychiatric disease. This Review highlights recent findings linking these channels to physiology and disease. In addition, it discusses some of the implications for therapy and points out questions that remain unanswered.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Structure and function of ASIC1A.
Figure 2: Roles for peripheral ASICs in pain.
Figure 3: ASIC1A expression in the mouse brain.
Figure 4: Contrasting roles of brain pH and ASICs in seizures and neurotoxicity.


  1. 1

    Gruol, D. L., Barker, J. L., Huang, L. Y., MacDonald, J. F. & Smith, T. G. Jr. Hydrogen ions have multiple effects on the excitability of cultured mammalian neurons. Brain Res. 183, 247–252 (1980).

    CAS  Google Scholar 

  2. 2

    Krishtal, O. & Pidoplichko, V. A receptor for protons in the nerve cell membrane. Neuroscience 5, 2325–2327 (1980).

    CAS  Google Scholar 

  3. 3

    Waldmann, R., Champigny, G., Bassilana, F., Heurteaux, C. & Lazdunski, M. A proton-gated cation channel involved in acid-sensing. Nature 386, 173–177 (1997). This study reports the cloning and identification of ASIC1A.

    CAS  Google Scholar 

  4. 4

    Price, M. P., Snyder, P. M. & Welsh, M. J. Cloning and expression of a novel human brain Na+ channel. J. Biol. Chem. 271, 7879–7882 (1996).

    CAS  Google Scholar 

  5. 5

    Waldmann, R., Champigny, G., Voilley, N., Lauritzen, I. & Lazdunski, M. The mammalian degenerin MDEG, an amiloride-sensitive cation channel activated by mutations causing neurodegeneration in Caenorhabditis elegans. J. Biol. Chem. 271, 10433–10436 (1996).

    CAS  Google Scholar 

  6. 6

    García-Añoveros, J., Derfler, B., Neville-Golden, J., Hyman, B. T. & Corey, D. P. BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels. Proc. Natl Acad. Sci. USA 94, 1459–1464 (1997).

    Google Scholar 

  7. 7

    Lingueglia, E. et al. A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J. Biol. Chem. 272, 29778–29783 (1997).

    CAS  Google Scholar 

  8. 8

    Waldmann, R. & Lazdunski, M. H+-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr. Opin. Neurobiol. 8, 418–424 (1998).

    CAS  Google Scholar 

  9. 9

    Sherwood, T. W., Frey, E. N. & Askwith, C. C. Structure and activity of the acid-sensing ion channels. Am. J. Physiol. Cell Physiol. 303, C699–C710 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  10. 10

    Chu, X. P., Papasian, C. J., Wang, J. Q. & Xiong, Z. G. Modulation of acid-sensing ion channels: molecular mechanisms and therapeutic potential. Int. J. Physiol. Pathophysiol. Pharmacol. 3, 288–309 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  11. 11

    Grunder, S. & Chen, X. Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. Int. J. Physiol. Pathophysiol. Pharmacol. 2, 73–94 (2010).

    PubMed Central  PubMed  Google Scholar 

  12. 12

    Deval, E. et al. Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol. Ther. 128, 549–558 (2010).

    CAS  Google Scholar 

  13. 13

    Wemmie, J. A., Price, M. P. & Welsh, M. J. Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci. 29, 578–586 (2006).

    CAS  Google Scholar 

  14. 14

    Chu, X. P. & Xiong, Z. G. Physiological and pathological functions of acid-sensing ion channels in the central nervous system. Curr. Drug Targets 13, 263–271 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  15. 15

    Xiong, Z. G., Pignataro, G., Li, M., Chang, S. Y. & Simon, R. P. Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr. Opin. Pharmacol. 8, 25–32 (2008).

    CAS  Google Scholar 

  16. 16

    Sluka, K. A., Winter, O. C. & Wemmie, J. A. Acid-sensing ion channels: a new target for pain and CNS diseases. Curr. Opin. Drug Discov. Devel. 12, 693–704 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  17. 17

    Zha, X. M. Acid-sensing ion channels: trafficking and synaptic function. Mol. Brain 6, 1 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  18. 18

    Price, M. P. et al. The mammalian sodium channel BNC1 is required for normal touch sensation. Nature 407, 1007–1011 (2000).

    CAS  Google Scholar 

  19. 19

    Price, M. P. et al. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32, 1071–1083 (2001).

    CAS  Google Scholar 

  20. 20

    Wemmie, J. A. et al. The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Neuron 34, 463–477 (2002). This study describes the electrophysiological and behavioural effects of genetically disrupting ASIC1A in mice.

    CAS  Google Scholar 

  21. 21

    Wemmie, J. A. et al. Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning. J. Neurosci. 23, 5496–5502 (2003). This paper describes the expression pattern of ASIC1A in the mouse brain and implicates ASIC1A in fear conditioning.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. 22

    Alvarez de la Rosa, D. et al. Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system. J. Physiol. 546, 77–87 (2003).

    CAS  Google Scholar 

  23. 23

    Benson, C. J., Eckert, S. P. & McCleskey, E. W. Acid-evoked currents in cardiac sensory neurons: a possible mediator of myocardial ischemic sensation. Circ. Res. 84, 921–928 (1999).

    CAS  Google Scholar 

  24. 24

    Delaunay, A. et al. Human ASIC3 channel dynamically adapts its activity to sense the extracellular pH in both acidic and alkaline directions. Proc. Natl Acad. Sci. USA 109, 13124–13129 (2012).

    CAS  Google Scholar 

  25. 25

    Wang, W. Z. et al. 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 (2006).

    CAS  Google Scholar 

  26. 26

    Chen, X. & Gründer, S. Permeating protons contribute to tachyphylaxis of the acid-sensing ion channel (ASIC) 1a. J. Physiol. 579, 657–670 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. 27

    Hesselager, M., Timmermann, D. B. & Ahring, P. K. pH-dependency and desensitization kinetics of heterologously expressed combinations of ASIC subunits. J. Biol. Chem. 279, 11006–11015 (2004).

    CAS  Google Scholar 

  28. 28

    Benson, C. J. et al. Heteromultimerics of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons. Proc. Natl Acad. Sci. USA 99, 2338–2343 (2002).

    CAS  Google Scholar 

  29. 29

    Bassilana, F. et al. The acid-sensitive ionic channel subunit ASIC and the mammalian degenerin MDEG form a heteromultimeric H+-gated Na+ channel with novel properties. J. Biol. Chem. 272, 28819–28822 (1997).

    CAS  Google Scholar 

  30. 30

    Jasti, J., Furukawa, H., Gonzales, E. B. & Gouaux, E. Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature 449, 316–323 (2007). This paper identifies the crystal structure of chicken ASIC1 minus the N and C termini.

    CAS  PubMed  Google Scholar 

  31. 31

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

    CAS  PubMed Central  PubMed  Google Scholar 

  32. 32

    Zha, X. M. et al. Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits. Proc. Natl Acad. Sci. USA 106, 3573–3578 (2009).

    CAS  PubMed  Google Scholar 

  33. 33

    Bianchi, L. Mechanotransduction: touch and feel at the molecular level as modeled in Caenorhabditis elegans. Mol. Neurobiol. 36, 254–271 (2007).

    CAS  PubMed  Google Scholar 

  34. 34

    Lu, Y. et al. The ion channel ASIC2 is required for baroreceptor and autonomic control of the circulation. Neuron 64, 885–897 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  35. 35

    Fromy, B., Lingueglia, E., Sigaudo-Roussel, D., Saumet, J. L. & Lazdunski, M. Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers. Nature Med. 18, 1205–1207 (2012).

    CAS  PubMed  Google Scholar 

  36. 36

    Roza, C. et al. Knockout of the ASIC2 channel in mice does not impair cutaneous mechanosensation, visceral mechanonociception and hearing. J. Physiol. 558, 659–669 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  37. 37

    Xiong, Z. G. et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118, 687–698 (2004). This is one of the earliest studies showing that targeting ASIC1A in a model of ischaemic stroke has a neuroprotective effect.

    CAS  PubMed  Google Scholar 

  38. 38

    Wu, P. Y. et al. Acid-sensing ion channel-1a is not required for normal hippocampal LTP and spatial memory. J. Neurosci. 33, 1828–1832 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  39. 39

    Zha, X. M., Wemmie, J. A., Green, S. H. & Welsh, M. J. Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines. Proc. Natl Acad. Sci. USA 103, 16556–16561 (2006). The authors of this study detected ASIC1A in dendritic spines and implicated it in synaptic plasticity.

    CAS  PubMed  Google Scholar 

  40. 40

    Cho, J. H. & Askwith, C. C. Presynaptic release probability is increased in hippocampal neurons from ASIC1 knockout mice. J. Neurophysiol. 99, 426–441 (2008).

    CAS  Google Scholar 

  41. 41

    Coryell, M. W. et al. Restoring acid-sensing ion channel-1a in the amygdala of knock-out mice rescues fear memory but not unconditioned fear responses. J. Neurosci. 28, 13738–13741 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. 42

    Ziemann, A. E. et al. The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior. Cell 139, 1012–1021 (2009). This study implicates ASIC1A in CO 2 -evoked fear behaviours and describes a chemosensory role for ASIC1A in the amygdala.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. 43

    Wemmie, J. et al. Overexpression of acid-sensing ion channel 1a in transgenic mice increases fear-related behavior. Proc. Natl Acad. Sci. USA 101, 3621–3626 (2004).

    CAS  Google Scholar 

  44. 44

    Vralsted, V. C. et al. Expressing acid-sensing ion channel 3 in the brain alters acid-evoked currents and impairs fear conditioning. Genes Brain Behav. 10, 444–450 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  45. 45

    Askwith, C. C., Wemmie, J. A., Price, M. P., Rokhlina, T. & Welsh, M. J. ASIC2 modulates ASIC1 H+-activated currents in hippocampal neurons. J. Biol. Chem. 279, 18296–18305 (2003).

    Google Scholar 

  46. 46

    Baron, A. et al. Protein kinase C stimulates the acid-sensing ion channel ASIC2a via the PDZ domain-containing protein PICK1. J. Biol. Chem. 277, 50463–50468 (2002).

    CAS  Google Scholar 

  47. 47

    Zha, X. M. et al. ASIC2 subunits target acid-sensing ion channels to the synapse via an association with PSD-95. J. Neurosci. 29, 8438–8446 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  48. 48

    Bohlen, C. J. et al. A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain. Nature 479, 410–414 (2011). The venom peptide MitTx activates ASIC1A in peripheral neurons to cause pain, and it increases the pH sensitivity of ASIC2.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. 49

    Wemmie, J. A., Zha, X. & Welsh, M. J. in Structural and Functional Organization of the Synapse (eds Hell, J. W. & Ehlers, M. D.) 661–681 (Springer, 2008).

    Google Scholar 

  50. 50

    Zeng, W. Z. & Xu, T. L. Proton production, regulation and pathophysiological roles in the mammalian brain. Neurosci. Bull. 28, 1–13 (2012).

    PubMed Central  PubMed  Google Scholar 

  51. 51

    Wemmie, J. A. Neurobiology of panic and pH chemosensation in the brain. Dialogues Clin. Neurosci. 13, 475–483 (2011).

    PubMed Central  PubMed  Google Scholar 

  52. 52

    Ziemann, A. E. et al. Seizure termination by acidosis depends on ASIC1a. Nature Neurosci. 11, 816–822 (2008). This paper describes a role for ASICs in seizures and suggests that ASIC1A promotes seizure termination.

    CAS  PubMed  Google Scholar 

  53. 53

    Vukicevic, M. & Kellenberger, S. Modulatory effects of acid-sensing ion channels (ASICs) on action potential generation in hippocampal neurons. Am. J. Physiol. Cell. Physiol. 287, C682–C690 (2004).

    CAS  PubMed  Google Scholar 

  54. 54

    Gao, J. et al. Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death. Neuron 48, 635–646 (2005).

    CAS  PubMed  Google Scholar 

  55. 55

    Chen, C. C. et al. A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc. Natl Acad. Sci. USA 99, 8992–8997 (2002).

    CAS  PubMed  Google Scholar 

  56. 56

    Kang, S. et al. Simultaneous disruption of mouse ASIC1a, ASIC2 and ASIC3 genes enhances cutaneous mechanosensitivity. PLoS ONE 7, e35225 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  57. 57

    Deval, E. et al. ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J. 27, 3047–3055 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  58. 58

    Page, A. J. et al. The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function. Gastroenterology 127, 1739–1747 (2004).

    CAS  Google Scholar 

  59. 59

    Walder, R. Y. et al. ASIC1 and ASIC3 play different roles in the development of hyperalgesia after inflammatory muscle injury. J. Pain 11, 210–218 (2010).

    CAS  Google Scholar 

  60. 60

    Mazzuca, M. et al. A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nature Neurosci. 10, 943–945 (2007). This study suggests that pharmacologically and genetically inhibiting ASIC1A has analgesic effects by increasing endogenous opioid levels.

    CAS  Google Scholar 

  61. 61

    Duan, B. et al. Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity. J. Neurosci. 27, 11139–11148 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  62. 62

    Yu, Y. et al. A nonproton ligand sensor in the acid-sensing ion channel. Neuron 68, 61–72 (2010). This paper suggests that GMQ directly activates ASIC3 on peripheral neurons to cause pain.

    CAS  Google Scholar 

  63. 63

    Li, W. G., Yu, Y., Zhang, Z. D., Cao, H. & Xu, T. L. ASIC3 channels integrate agmatine and multiple inflammatory signals through the nonproton ligand sensing domain. Mol. Pain 6, 88 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  64. 64

    Escoubas, P. et al. Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J. Biol. Chem. 275, 25116–25121 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Wu, L. J. et al. Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord. J. Biol. Chem. 279, 43716–43724 (2004).

    CAS  PubMed  Google Scholar 

  66. 66

    Duan, B. et al. PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity. J. Neurosci. 32, 6351–6363 (2012). This paper demonstrates that increased ASIC1A surface expression in the dorsal horn of the spinal cord may contribute to the central sensitization to pain.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. 67

    Diochot, S. et al. Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature 490, 552–555 (2012). This study strongly suggests that blocking ASICs with black mamba venom toxins reduces pain and that the effect is not opioid-dependent.

    CAS  PubMed  Google Scholar 

  68. 68

    Holland, P. R. et al. Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann. Neurol. 72, 559–563 (2012).

    CAS  PubMed  Google Scholar 

  69. 69

    Ugawa, S. et al. Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. J. Clin. Invest. 110, 1185–1190 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  70. 70

    Jones, N. G., Slater, R., Cadiou, H., McNaughton, P. & McMahon, S. B. Acid-induced pain and its modulation in humans. J. Neurosci. 24, 10974–10979 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  71. 71

    Yermolaieva, O., Leonard, A. S., Schnizler, M. K., Abboud, F. M. & Welsh, M. J. Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc. Natl Acad. Sci. USA 101, 6752–6757 (2004).

    CAS  Google Scholar 

  72. 72

    Isaev, N. K. et al. Role of acidosis, NMDA receptors, and acid-sensitive ion channel 1a (ASIC1a) in neuronal death induced by ischemia. Biochemistry 73, 1171–1175 (2008).

    CAS  Google Scholar 

  73. 73

    Friese, M. A. et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nature Med. 13, 1483–1489 (2007). This study implicates ASIC1A in a mouse model of neuroinflammatory disease.

    CAS  Google Scholar 

  74. 74

    Wong, H. K. et al. Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism. Hum. Mol. Genet. 17, 3223–3235 (2008).

    CAS  Google Scholar 

  75. 75

    Arias, R. L. et al. Amiloride is neuroprotective in an MPTP model of Parkinson's disease. Neurobiol. Dis. 31, 334–341 (2008).

    CAS  Google Scholar 

  76. 76

    Hu, R. et al. Role of acid-sensing ion channel 1a in the secondary damage of traumatic spinal cord injury. Ann. Surg. 254, 353–362 (2011).

    Google Scholar 

  77. 77

    Zeng, W. Z. et al. Molecular mechanism of constitutive endocytosis of acid-sensing ion channel 1a and its protective function in acidosis-induced neuronal death. J. Neurosci. 33, 7066–7078 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  78. 78

    Sherwood, T. W., Lee, K. G., Gormley, M. G. & Askwith, C. C. Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death. J. Neurosci. 31, 9723–9734 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  79. 79

    Immke, D. C. & McCleskey, E. W. Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nature Neurosci. 4, 869–870 (2001).

    CAS  Google Scholar 

  80. 80

    Allen, N. J. & Attwell, D. Modulation of ASIC channels in rat cerebellar Purkinje neurons by ischaemia-related signals. J. Physiol. 543, 521–529 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  81. 81

    Hauser, K. F. et al. Pathobiology of dynorphins in trauma and disease. Front. Biosci. 10, 216–235 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  82. 82

    Kindy, M. S., Hu, Y. & Dempsey, R. J. Blockade of ornithine decarboxylase enzyme protects against ischemic brain damage. J. Cereb. Blood Flow Metab. 14, 1040–1045 (1994).

    CAS  Google Scholar 

  83. 83

    Babini, E., Paukert, M., Geisler, H. S. & Gründer, S. Alternative splicing and interaction with di- and polyvalent cations control the dynamic range of acid-sensing ion channel 1 (ASIC1). J. Biol. Chem. 277, 41597–41603 (2002).

    CAS  Google Scholar 

  84. 84

    Duan, B. et al. Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. J. Neurosci. 31, 2101–2112 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. 85

    Chang, Y. et al. Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats. J. Biomed. Sci. 16, 9 (2009).

    PubMed Central  PubMed  Google Scholar 

  86. 86

    Gu, L., Yang, Y., Sun, Y. & Zheng, X. Puerarin inhibits acid-sensing ion channels and protects against neuron death induced by acidosis. Planta Med. 76, 583–588 (2010).

    CAS  Google Scholar 

  87. 87

    Zhang, Y. et al. Ginsenoside-Rd attenuates TRPM7 and ASIC1a but promotes ASIC2a expression in rats after focal cerebral ischemia. Neurol. Sci. 33, 1125–1131 (2012).

    CAS  Google Scholar 

  88. 88

    Yifeng, M. et al. Neuroprotective effect of sophocarpine against transient focal cerebral ischemia via down-regulation of the acid-sensing ion channel 1 in rats. Brain Res. 1382, 245–251 (2011).

    Google Scholar 

  89. 89

    Berdiev, B. K. et al. Acid-sensing ion channels in malignant gliomas. J. Biol. Chem. 278, 15023–15034 (2003).

    CAS  Google Scholar 

  90. 90

    Bubien, J. K. et al. Cation selectivity and inhibition of malignant glioma Na+ channels by Psalmotoxin 1. Am. J. Physiol. Cell Physiol. 287, C1282–C1291 (2004).

    CAS  Google Scholar 

  91. 91

    Vila-Carriles, W. H. et al. Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells. J. Biol. Chem. 281, 19220–19232 (2006).

    CAS  Google Scholar 

  92. 92

    Kapoor, N. et al. Knockdown of ASIC1 and epithelial sodium channel subunits inhibits glioblastoma whole cell current and cell migration. J. Biol. Chem. 284, 24526–24541 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  93. 93

    Rooj, A. K. et al. Glioma-specific cation conductance regulates migration and cell cycle progression. J. Biol. Chem. 287, 4053–4065 (2012).

    CAS  Google Scholar 

  94. 94

    Biagini, G., Babinski, K., Avoli, M., Marcinkiewicz, M. & Séguéla, P. Regional and subunit-specific downregulation of acid-sensing ion channels in the pilocarpine model of epilepsy. Neurobiol. Dis. 8, 45–58 (2001).

    CAS  Google Scholar 

  95. 95

    Weng, J. Y., Lin, Y. C. & Lien, C. C. Cell type-specific expression of acid-sensing ion channels in hippocampal interneurons. J. Neurosci. 30, 6548–6558 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  96. 96

    Bolshakov, K. V. et al. Characterization of acid-sensitive ion channels in freshly isolated rat brain neurons. Neuroscience 110, 723–730 (2002).

    CAS  Google Scholar 

  97. 97

    Ali, A., Pillai, K. P., Ahmad, F. J., Dua, Y. & Vohora, D. Anticonvulsant effect of amiloride in pentetrazole-induced status epilepticus in mice. Pharmacol. Rep. 58, 242–245 (2006).

    CAS  Google Scholar 

  98. 98

    N'Gouemo, P. Amiloride delays the onset of pilocarpine-induced seizures in rats. Brain Res. 1222, 230–232 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  99. 99

    Luszczki, J. J., Sawicka, K. M., Kozinska, J., Dudra-Jastrzebska, M. & Czuczwar, S. J. Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model. J. Neural Transm. 116, 57–66 (2009).

    CAS  Google Scholar 

  100. 100

    Lv, R. J. et al. ASIC1a polymorphism is associated with temporal lobe epilepsy. Epilepsy Res. 96, 74–80 (2011).

    CAS  Google Scholar 

  101. 101

    Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005).

    Google Scholar 

  102. 102

    Coryell, M. et al. Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit. Biol. Psychiatry 62, 1140–1148 (2007).

    CAS  Google Scholar 

  103. 103

    Drury, A. N. The percentage of carbon dioxide in the alveolar air, and the tolerance to accumulating carbon dioxide in case of co-called “irritable heart”. Heart 7, 165–173 (1918).

    Google Scholar 

  104. 104

    Coryell, M. W. et al. Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior. J. Neurosci. 29, 5381–5388 (2009). This study shows that loss of ASIC1A has antidepressant-like effects in multiple mouse models of depression.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. 105

    Hettema, J. M. et al. Lack of association between the amiloride-sensitive cation channel 2 (ACCN2) gene and anxiety spectrum disorders. Psychiatr. Genet. 18, 73–79 (2008).

    Google Scholar 

  106. 106

    Smoller, J. W. et al. Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am. J. Med. Genet. 105, 195–206 (2001).

    CAS  Google Scholar 

  107. 107

    Squassina, A. et al. Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder. Pharmacogenomics 12, 1559–1569 (2011).

    CAS  Google Scholar 

  108. 108

    Garriock, H. A. et al. A genomewide association study of citalopram response in major depressive disorder. Biol. Psychiatry 67, 133–138 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  109. 109

    Gregersen, N. et al. A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene. Eur. J. Hum. Genet. 20, 84–90 (2012).

    CAS  Google Scholar 

  110. 110

    Stone, J. L., Merriman, B., Cantor, R. M., Geschwind, D. H. & Nelson, S. F. High density SNP association study of a major autism linkage region on chromosome 17. Hum. Mol. Genet. 16, 704–715 (2007).

    CAS  Google Scholar 

  111. 111

    Magnotta, V. A. et al. Detecting activity-evoked pH changes in human brain. Proc. Natl Acad. Sci. USA 109, 8270–8273 (2012). This study shows that brain activation produces a functional acidosis that is detectable with MRI.

    CAS  Google Scholar 

  112. 112

    Arun, T. et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 136, 106–115 (2013).

    Google Scholar 

  113. 113

    Wang, X. et al. Serotonin facilitates peripheral pain sensitivity in a manner that depends on the nonproton ligand sensing domain of ASIC3 channel. J. Neurosci. 33, 4265–4279 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  114. 114

    Wu, W. L., Lin, Y. W., Min, M. Y. & Chen, C. C. Mice lacking Asic3 show reduced anxiety-like behavior on the elevated plus maze and reduced aggression. Genes Brain Behav. 9, 603–614 (2010).

    CAS  Google Scholar 

  115. 115

    Sherwood, T. W. & Askwith, C. C. Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal death. J. Neurosci. 29, 14371–14380 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  116. 116

    Dawson, R. J. et al. Structure of the Acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1. Nature Commun. 3, 936 (2012).

    Google Scholar 

  117. 117

    Askwith, C. C. et al. Neuropeptide FF and FMRFamide potentiate acid-evoked currents from sensory neurons and proton-gated DEG/ENaC channels. Neuron 26, 133–141 (2000).

    CAS  Google Scholar 

  118. 118

    Staruschenko, A., Dorofeeva, N. A., Bolshakov, K. V. & Stockand, J. D. Subunit-dependent cadmium and nickel inhibition of acid-sensing ion channels. Dev. Neurobiol. 67, 97–107 (2007).

    CAS  Google Scholar 

  119. 119

    Wang, W., Yu, Y. & Xu, T. L. Modulation of acid-sensing ion channels by Cu2+ in cultured hypothalamic neurons of the rat. Neuroscience 145, 631–641 (2007).

    CAS  Google Scholar 

  120. 120

    Babinski, K., Catarsi, S., Biagini, G. & Seguela, P. Mammalian ASIC2a and ASIC3 subunits co-assemble into heteromeric proton- gated channels sensitive to Gd3+. J. Biol. Chem. 275, 28519–28525 (2000).

    CAS  Google Scholar 

  121. 121

    Wang, W., Duan, B., Xu, H., Xu, L. & Xu, T. L. Calcium-permeable Acid-sensing ion channel is a molecular target of the neurotoxic metal ion lead. J. Biol. Chem. 281, 2497–2505 (2006).

    CAS  Google Scholar 

  122. 122

    Chu, X. P. et al. Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels. J. Neurosci. 24, 8678–8689 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  123. 123

    Paukert, M., Babini, E., Pusch, M. & Grunder, S. Identification of the Ca2+ blocking site of acid-sensing ion channel (ASIC) 1: implications for channel gating. J. Gen. Physiol. 124, 383–394 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  124. 124

    Sherwood, T. et al. Identification of protein domains that control proton and calcium sensitivity of ASIC1a. J. Biol. Chem. 284, 27899–27907 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  125. 125

    Smith, E. S., Cadiou, H. & McNaughton, P. A. Arachidonic acid potentiates acid-sensing ion channels in rat sensory neurons by a direct action. Neuroscience 145, 686–698 (2007).

    CAS  Google Scholar 

  126. 126

    Cadiou, H. et al. Modulation of acid-sensing ion channel activity by nitric oxide. J. Neurosci. 27, 13251–13260 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  127. 127

    Birdsong, W. T. et al. Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels. Neuron 68, 739–749 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  128. 128

    Chen, X., Kalbacher, H. & Grunder, S. The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity. J. Gen. Physiol. 126, 71–79 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  129. 129

    Diochot, S. et al. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J. 23, 1516–1525 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  130. 130

    Voilley, N., de Weille, J., Mamet, J. & Lazdunski, M. Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J. Neurosci. 21, 8026–8033 (2001).

    CAS  Google Scholar 

  131. 131

    Qadri, Y. J., Song, Y., Fuller, C. M. & Benos, D. J. Amiloride docking to acid-sensing ion channel-1. J. Biol. Chem. 285, 9627–9635 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  132. 132

    Adams, C. M., Snyder, P. M. & Welsh, M. J. Paradoxical stimulation of a DEG/ENaC channel by amiloride. J. Biol. Chem. 274, 15500–15504 (1999).

    CAS  PubMed  Google Scholar 

  133. 133

    Dube, G. R. et al. Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain 117, 88–96 (2005).

    CAS  PubMed  Google Scholar 

  134. 134

    Ugawa, S. et al. Nafamostat mesilate reversibly blocks acid-sensing ion channel currents. Biochem. Biophys. Res. Commun. 363, 203–208 (2007).

    CAS  PubMed  Google Scholar 

  135. 135

    Nedergaard, M., Kraig, R. P., Tanabe, J. & Pulsinelli, W. A. Dynamics of interstitial and intracellular pH in evolving brain infarct. Am. J. Physiol. 260, R581–R588 (1991).

    CAS  PubMed Central  PubMed  Google Scholar 

  136. 136

    Pignataro, G., Simon, R. P. & Xiong, Z. G. Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia. Brain 130, 151–158 (2007).

    PubMed  Google Scholar 

  137. 137

    Vergo, S. et al. Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain 134, 571–584 (2011).

    PubMed  Google Scholar 

  138. 138

    Bernardinelli, L. et al. Association between the ACCN1 gene and multiple sclerosis in Central East Sardinia. PLoS ONE 2, e480 (2007).

    PubMed Central  PubMed  Google Scholar 

  139. 139

    Jenkins, B. G. et al. 1H NMR spectroscopy studies of Huntington's disease: correlations with CAG repeat numbers. Neurology 50, 1357–1365 (1998).

    CAS  PubMed  Google Scholar 

  140. 140

    Tsang, T. M. et al. Metabolic characterization of the R6/2 transgenic mouse model of Huntington's disease by high-resolution MAS 1H NMR spectroscopy. J. Proteome Res. 5, 483–492 (2006).

    CAS  Google Scholar 

  141. 141

    Bowen, B. C. et al. Proton MR spectroscopy of the brain in 14 patients with Parkinson disease. AJNR Am. J. Neuroradiol. 16, 61–68 (1995).

    CAS  Google Scholar 

  142. 142

    Pidoplichko, V. I. & Dani, J. A. Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. Proc. Natl Acad. Sci. USA 103, 11376–11380 (2006).

    CAS  Google Scholar 

  143. 143

    Joch, M. et al. Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Mol. Biol. Cell 18, 3105–3118 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  144. 144

    Yan, J. et al. Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache. Pain 152, 106–113 (2011).

    CAS  Google Scholar 

  145. 145

    Vila-Carriles, W. H., Zhou, Z. H., Bubien, J. K., Fuller, C. M. & Benos, D. J. Participation of the chaperone Hsc70 in the trafficking and functional expression of ASIC2 in glioma cells. J. Biol. Chem. 282, 34381–34391 (2007).

    CAS  Google Scholar 

  146. 146

    Wang, R. I. H. & Sonnenschein, R. R. pH of cerebral cortex during induced convulsions. J. Neurophysiol. 18, 130–137 (1955).

    CAS  PubMed  Google Scholar 

  147. 147

    Lennox, W. G. The effect on epileptic seizures of varying the composition of the respired air. J. Clin. Invest. 6, 23–24 (1929).

    Google Scholar 

  148. 148

    Tolner, E. A. et al. Five percent CO is a potent, fast-acting inhalation anticonvulsant. Epilepsia 52, 104–114 (2011).

    PubMed  Google Scholar 

Download references


J.A.W. is supported by the Department of Veterans Affairs (Merit Award), the National Institutes of Mental Health (1R01MH085724 01) and a McKnight Neuroscience of Brain Disorders Award.

Author information



Corresponding author

Correspondence to John A. Wemmie.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides


Degenerin–epithelial Na+ channel family

(DEG–ENaC family). A family of ion channels that includes acid-sensing ion channels and is characterized by two transmembrane domains, a relatively large cysteine-rich extracellular domain and several highly conserved amino acid sequence motifs.


Refers to detection of painful and injurious stimuli and translation into a neuronal signal.


Refers to detection of mechanical stimuli and translation into a neuronal signal.


A physiological state characterized by acidic pH (high H+ concentration).


A physiological state characterized by basic pH (low H+ concentration).


Receptors that are sensitive to changes in blood pressure.

Long-term potentiation

A long-lasting, activity-dependent strengthening of synaptic transmission.

Postictal depression

The reduction in electroencephalographic activity that occurs immediately after a seizure.


A GABA receptor antagonist used to elicit seizures.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wemmie, J., Taugher, R. & Kreple, C. Acid-sensing ion channels in pain and disease. Nat Rev Neurosci 14, 461–471 (2013).

Download citation

Further reading