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.
At a glance
- Hydrogen ions have multiple effects on the excitability of cultured mammalian neurons. Brain Res. 183, 247–252 (1980). , , , &
- A receptor for protons in the nerve cell membrane. Neuroscience 5, 2325–2327 (1980). &
- A proton-gated cation channel involved in acid-sensing. Nature 386, 173–177 (1997).
This study reports the cloning and identification of ASIC1A.
, , , &
- Cloning and expression of a novel human brain Na+ channel. J. Biol. Chem. 271, 7879–7882 (1996). , &
- The mammalian degenerin MDEG, an amiloride-sensitive cation channel activated by mutations causing neurodegeneration in Caenorhabditis elegans. J. Biol. Chem. 271, 10433–10436 (1996). , , , &
- 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). , , , &
- A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J. Biol. Chem. 272, 29778–29783 (1997). et al.
- H+-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr. Opin. Neurobiol. 8, 418–424 (1998). &
- Structure and activity of the acid-sensing ion channels. Am. J. Physiol. Cell Physiol. 303, C699–C710 (2012). , &
- Modulation of acid-sensing ion channels: molecular mechanisms and therapeutic potential. Int. J. Physiol. Pathophysiol. Pharmacol. 3, 288–309 (2011). , , &
- Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. Int. J. Physiol. Pathophysiol. Pharmacol. 2, 73–94 (2010). &
- Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol. Ther. 128, 549–558 (2010). et al.
- Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci. 29, 578–586 (2006). , &
- Physiological and pathological functions of acid-sensing ion channels in the central nervous system. Curr. Drug Targets 13, 263–271 (2012). &
- Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr. Opin. Pharmacol. 8, 25–32 (2008). , , , &
- Acid-sensing ion channels: a new target for pain and CNS diseases. Curr. Opin. Drug Discov. Devel. 12, 693–704 (2009). , &
- Acid-sensing ion channels: trafficking and synaptic function. Mol. Brain 6, 1 (2013).
- The mammalian sodium channel BNC1 is required for normal touch sensation. Nature 407, 1007–1011 (2000). et al.
- The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32, 1071–1083 (2001). 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.
- 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.
- Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system. J. Physiol. 546, 77–87 (2003). et al.
- Acid-evoked currents in cardiac sensory neurons: a possible mediator of myocardial ischemic sensation. Circ. Res. 84, 921–928 (1999). , &
- 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). 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). et al.
- Permeating protons contribute to tachyphylaxis of the acid-sensing ion channel (ASIC) 1a. J. Physiol. 579, 657–670 (2007). &
- pH-dependency and desensitization kinetics of heterologously expressed combinations of ASIC subunits. J. Biol. Chem. 279, 11006–11015 (2004). , &
- Heteromultimerics of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons. Proc. Natl Acad. Sci. USA 99, 2338–2343 (2002). 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). et al.
- 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.
, , &
- Pore architecture and ion sites in acid-sensing ion channels and P2X receptors. Nature 460, 599–604 (2009). , &
- Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits. Proc. Natl Acad. Sci. USA 106, 3573–3578 (2009). et al.
- Mechanotransduction: touch and feel at the molecular level as modeled in Caenorhabditis elegans. Mol. Neurobiol. 36, 254–271 (2007).
- The ion channel ASIC2 is required for baroreceptor and autonomic control of the circulation. Neuron 64, 885–897 (2009). et al.
- Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers. Nature Med. 18, 1205–1207 (2012). , , , &
- Knockout of the ASIC2 channel in mice does not impair cutaneous mechanosensation, visceral mechanonociception and hearing. J. Physiol. 558, 659–669 (2004). 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.
- Acid-sensing ion channel-1a is not required for normal hippocampal LTP and spatial memory. J. Neurosci. 33, 1828–1832 (2013). et al.
- 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.
, , &
- Presynaptic release probability is increased in hippocampal neurons from ASIC1 knockout mice. J. Neurophysiol. 99, 426–441 (2008). &
- 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). 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 CO2-evoked fear behaviours and describes a chemosensory role for ASIC1A in the amygdala.
- Overexpression of acid-sensing ion channel 1a in transgenic mice increases fear-related behavior. Proc. Natl Acad. Sci. USA 101, 3621–3626 (2004). 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). et al.
- ASIC2 modulates ASIC1 H+-activated currents in hippocampal neurons. J. Biol. Chem. 279, 18296–18305 (2003). , , , &
- Protein kinase C stimulates the acid-sensing ion channel ASIC2a via the PDZ domain-containing protein PICK1. J. Biol. Chem. 277, 50463–50468 (2002). et al.
- ASIC2 subunits target acid-sensing ion channels to the synapse via an association with PSD-95. J. Neurosci. 29, 8438–8446 (2009). 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.
- 661–681 (Springer, 2008). , & in Structural and Functional Organization of the Synapse (eds Hell, J. W. & Ehlers, M. D.)
- Proton production, regulation and pathophysiological roles in the mammalian brain. Neurosci. Bull. 28, 1–13 (2012). &
- Neurobiology of panic and pH chemosensation in the brain. Dialogues Clin. Neurosci. 13, 475–483 (2011).
- 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.
- Modulatory effects of acid-sensing ion channels (ASICs) on action potential generation in hippocampal neurons. Am. J. Physiol. Cell. Physiol. 287, C682–C690 (2004). &
- Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death. Neuron 48, 635–646 (2005). et al.
- A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc. Natl Acad. Sci. USA 99, 8992–8997 (2002). et al.
- Simultaneous disruption of mouse ASIC1a, ASIC2 and ASIC3 genes enhances cutaneous mechanosensitivity. PLoS ONE 7, e35225 (2012). et al.
- ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J. 27, 3047–3055 (2008). et al.
- The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function. Gastroenterology 127, 1739–1747 (2004). et al.
- ASIC1 and ASIC3 play different roles in the development of hyperalgesia after inflammatory muscle injury. J. Pain 11, 210–218 (2010). 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.
- Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity. J. Neurosci. 27, 11139–11148 (2007). 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.
- ASIC3 channels integrate agmatine and multiple inflammatory signals through the nonproton ligand sensing domain. Mol. Pain 6, 88 (2010). , , , &
- Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J. Biol. Chem. 275, 25116–25121 (2000). et al.
- Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord. J. Biol. Chem. 279, 43716–43724 (2004). 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.
- 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.
- Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann. Neurol. 72, 559–563 (2012). et al.
- Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. J. Clin. Invest. 110, 1185–1190 (2002). et al.
- Acid-induced pain and its modulation in humans. J. Neurosci. 24, 10974–10979 (2004). , , , &
- Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc. Natl Acad. Sci. USA 101, 6752–6757 (2004). , , , &
- Role of acidosis, NMDA receptors, and acid-sensitive ion channel 1a (ASIC1a) in neuronal death induced by ischemia. Biochemistry 73, 1171–1175 (2008). 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.
- 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). et al.
- Amiloride is neuroprotective in an MPTP model of Parkinson's disease. Neurobiol. Dis. 31, 334–341 (2008). et al.
- Role of acid-sensing ion channel 1a in the secondary damage of traumatic spinal cord injury. Ann. Surg. 254, 353–362 (2011). 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). et al.
- 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). , , &
- Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nature Neurosci. 4, 869–870 (2001). &
- Modulation of ASIC channels in rat cerebellar Purkinje neurons by ischaemia-related signals. J. Physiol. 543, 521–529 (2002). &
- Pathobiology of dynorphins in trauma and disease. Front. Biosci. 10, 216–235 (2005). et al.
- Blockade of ornithine decarboxylase enzyme protects against ischemic brain damage. J. Cereb. Blood Flow Metab. 14, 1040–1045 (1994). , &
- 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). , , &
- Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. J. Neurosci. 31, 2101–2112 (2011). et al.
- Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats. J. Biomed. Sci. 16, 9 (2009). et al.
- Puerarin inhibits acid-sensing ion channels and protects against neuron death induced by acidosis. Planta Med. 76, 583–588 (2010). , , &
- Ginsenoside-Rd attenuates TRPM7 and ASIC1a but promotes ASIC2a expression in rats after focal cerebral ischemia. Neurol. Sci. 33, 1125–1131 (2012). 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). et al.
- Acid-sensing ion channels in malignant gliomas. J. Biol. Chem. 278, 15023–15034 (2003). et al.
- Cation selectivity and inhibition of malignant glioma Na+ channels by Psalmotoxin 1. Am. J. Physiol. Cell Physiol. 287, C1282–C1291 (2004). et al.
- Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells. J. Biol. Chem. 281, 19220–19232 (2006). 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). et al.
- Glioma-specific cation conductance regulates migration and cell cycle progression. J. Biol. Chem. 287, 4053–4065 (2012). et al.
- Regional and subunit-specific downregulation of acid-sensing ion channels in the pilocarpine model of epilepsy. Neurobiol. Dis. 8, 45–58 (2001). , , , &
- Cell type-specific expression of acid-sensing ion channels in hippocampal interneurons. J. Neurosci. 30, 6548–6558 (2010). , &
- Characterization of acid-sensitive ion channels in freshly isolated rat brain neurons. Neuroscience 110, 723–730 (2002). et al.
- Anticonvulsant effect of amiloride in pentetrazole-induced status epilepticus in mice. Pharmacol. Rep. 58, 242–245 (2006). , , , &
- Amiloride delays the onset of pilocarpine-induced seizures in rats. Brain Res. 1222, 230–232 (2008).
- Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model. J. Neural Transm. 116, 57–66 (2009). , , , &
- ASIC1a polymorphism is associated with temporal lobe epilepsy. Epilepsy Res. 96, 74–80 (2011). 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). et al.
- Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit. Biol. Psychiatry 62, 1140–1148 (2007). et al.
- 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).
- 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.
- Lack of association between the amiloride-sensitive cation channel 2 (ACCN2) gene and anxiety spectrum disorders. Psychiatr. Genet. 18, 73–79 (2008). 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). 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). et al.
- A genomewide association study of citalopram response in major depressive disorder. Biol. Psychiatry 67, 133–138 (2010). 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). et al.
- High density SNP association study of a major autism linkage region on chromosome 17. Hum. Mol. Genet. 16, 704–715 (2007). , , , &
- 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.
- Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 136, 106–115 (2013). 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). et al.
- Mice lacking Asic3 show reduced anxiety-like behavior on the elevated plus maze and reduced aggression. Genes Brain Behav. 9, 603–614 (2010). , , &
- Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal death. J. Neurosci. 29, 14371–14380 (2009). &
- Structure of the Acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1. Nature Commun. 3, 936 (2012). et al.
- Neuropeptide FF and FMRFamide potentiate acid-evoked currents from sensory neurons and proton-gated DEG/ENaC channels. Neuron 26, 133–141 (2000). et al.
- Subunit-dependent cadmium and nickel inhibition of acid-sensing ion channels. Dev. Neurobiol. 67, 97–107 (2007). , , &
- Modulation of acid-sensing ion channels by Cu2+ in cultured hypothalamic neurons of the rat. Neuroscience 145, 631–641 (2007). , &
- Mammalian ASIC2a and ASIC3 subunits co-assemble into heteromeric proton- gated channels sensitive to Gd3+. J. Biol. Chem. 275, 28519–28525 (2000). , , &
- Calcium-permeable Acid-sensing ion channel is a molecular target of the neurotoxic metal ion lead. J. Biol. Chem. 281, 2497–2505 (2006). , , , &
- Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels. J. Neurosci. 24, 8678–8689 (2004). et al.
- Identification of the Ca2+ blocking site of acid-sensing ion channel (ASIC) 1: implications for channel gating. J. Gen. Physiol. 124, 383–394 (2004). , , &
- Identification of protein domains that control proton and calcium sensitivity of ASIC1a. J. Biol. Chem. 284, 27899–27907 (2009). et al.
- Arachidonic acid potentiates acid-sensing ion channels in rat sensory neurons by a direct action. Neuroscience 145, 686–698 (2007). , &
- Modulation of acid-sensing ion channel activity by nitric oxide. J. Neurosci. 27, 13251–13260 (2007). et al.
- Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels. Neuron 68, 739–749 (2010). et al.
- 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). , &
- A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J. 23, 1516–1525 (2004). et al.
- 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). , , &
- Amiloride docking to acid-sensing ion channel-1. J. Biol. Chem. 285, 9627–9635 (2010). , , &
- Paradoxical stimulation of a DEG/ENaC channel by amiloride. J. Biol. Chem. 274, 15500–15504 (1999). , &
- Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain 117, 88–96 (2005). et al.
- Nafamostat mesilate reversibly blocks acid-sensing ion channel currents. Biochem. Biophys. Res. Commun. 363, 203–208 (2007). et al.
- Dynamics of interstitial and intracellular pH in evolving brain infarct. Am. J. Physiol. 260, R581–R588 (1991). , , &
- Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia. Brain 130, 151–158 (2007). , &
- 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). et al.
- Association between the ACCN1 gene and multiple sclerosis in Central East Sardinia. PLoS ONE 2, e480 (2007). et al.
- 1H NMR spectroscopy studies of Huntington's disease: correlations with CAG repeat numbers. Neurology 50, 1357–1365 (1998). 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). et al.
- Proton MR spectroscopy of the brain in 14 patients with Parkinson disease. AJNR Am. J. Neuroradiol. 16, 61–68 (1995). et al.
- 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). &
- Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Mol. Biol. Cell 18, 3105–3118 (2007). et al.
- Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache. Pain 152, 106–113 (2011). et al.
- Participation of the chaperone Hsc70 in the trafficking and functional expression of ASIC2 in glioma cells. J. Biol. Chem. 282, 34381–34391 (2007). , , , &
- pH of cerebral cortex during induced convulsions. J. Neurophysiol. 18, 130–137 (1955). &
- The effect on epileptic seizures of varying the composition of the respired air. J. Clin. Invest. 6, 23–24 (1929).
- Five percent CO is a potent, fast-acting inhalation anticonvulsant. Epilepsia 52, 104–114 (2011). et al.