Acid-sensing ion channel

Last updated
Acid-sensing sodium channel
PDB 1qts EBI.jpg
Structure of acid-sensing ion channel 1. [1]
Identifiers
SymbolASC
Pfam PF00858
InterPro IPR001873
PROSITE PDOC00926
SCOP2 2qts / SCOPe / SUPFAM
TCDB 1.A.6
OPM superfamily 181
OPM protein 4fz1
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. [2] ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. [3] Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. [2] However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. On a broad scale, ASICs are potential drug targets due to their involvement in pathological states such as retinal damage, seizures, and ischemic brain injury. [4] [5]

Contents

Structure

Crystallized structure of Acid-sensing ion channel

Each acid-sensing ion channel is composed of a 500-560 amino acid sequence, which is constructed into a six transmembrane segment—two per subunit (TMD1 and TMD2), a cytoplasmic amino-carboxyl termini, and a large extracellular domain. [3] The intracellular amino-carboxyl termini domains are vital to the channel's intracellular protein interactions and modulations, ion permeability, and gating. However, the gating and mechanics of each acid-sensing ion channel is determined by the combination of ASIC subunits that form its structure. [3]

Pore

The mechanics of the pore function are fundamental to the channel's structure. Between the three ASIC1 subunits, a tunnel extends from the top of the extracellular domains to the cytoplasm of the cell. The central tunnel runs directly between the trimeric unit, where it has large constricted areas that change in size and shape depending on channel state. [3]

The two transmembrane domains (TMD1 and TMD2) of each of the three ASIC subunits are responsible for the channel's pore. TMD2 is primarily involved with lining of the lumen within the pore and inactivation gate of the channel, where as TMD1 holds the protein within the cell's lipid bilayer. [6] TMD1 is connected to the β-sheets of the extracellular domain that flex to widen the extracellular domain to allow for ion passage through the channel. [3] In-between the TMD2 segments resides a selectivity filter that forms the narrowest part of the pore, which is responsible for ASIC permissibility to mostly Na+. For ASIC1, nine amino acid residues, three contributed by each ASIC subunit (Gly443, Ala444, Ser445), form the selectivity filter. Nicknamed the "GAS belt", all three carbonyl oxygens line the pore, producing a negative potential that contributes to the conductance of cations. [3] The specific amino acid residue of aspartate on the extracellular side lumen of TMD2 in ASIC1 has been linked to the channel's low Ca2+ conductance. Additionally, The n-termini residues of the transmembrane region has also shown selectivity for Na+, since mutations within this region has altered function and of Na+ conductance. [3]

Extracellular region

ASIC's have a large, fist-like extracellular region that consumes most of the proteins structure. Within its "fist-like" structure there is a wrist, palm, finger, knuckle, thumb and β-ball domains. The "palm" makes up most of the extracellular domain, formed by seven β-sheets, where as the rest of the secondary structural domains are composed of α-helical segments. [3] Distinguished by its specific amino acid configurations, the extracellular region is fundamental to the induction of activation/inactivation along with pH gating. The specific β-sheet loop area between the "palm" and "thumb" domains has shown involvement in the signal transduction from the extracellular domain to the transmembrane regions, resulting in a conformational change of the ASIC to its open state. [3] However, it remains fairly inconclusive of which particular residues interact with protons to activate the channel. In 2009, studies may have established a relationship between the aromatic residues Tyr72, Pro287, and Trp288 and proton-gating of the ASIC. [3] These residues form an acidic pocket that express electrostatic potentials that are responsible for pH-dependency in channel activation and modulation. [7] This pocket in the extracellular domain acts as a reserve for cations to concentrate to further assist in Na+ influx. Glycosylation is also apparent within the extracellular region, playing an important role in the trafficking the channel to the membrane's surface as well as establishing the ASIC's sensitivity to pH levels. Further experimental evidence has indicated that Ca2+ may also play a pivotal role in modulating proton affinity of ASIC gating both within the pore and on the extracellular domain. [3]

Function

The role of the ASIC is to sense reduced levels of extracellular pH and result in a response or signal from the neuron. The ligand that binds to the activation site has long been thought to be exclusively protons; however, recent studies have shown that ASIC4 and ASIC1 can be activated at normal pH levels, indicating other types of ligand binders. [8] Under increased acidic conditions, a proton binds to the channel in the extracellular region, activating the ion channel to go through conformational change therefore opening transmembrane domain 2 (TMD2). This results in the influx of sodium ions through the lumen of TMD2. All ASICs are specifically permeable to sodium ions. The only variant is ASIC1a which also has a low permeability to calcium ions. The influx of these cations results in membrane depolarization. Voltage-gated Ca2+ channels are activated resulting in an influx of calcium into the cell. This causes depolarization of the neuron and an excitatory response released. In ASIC1a, Ca2+ increase inside the cell is a result of calcium influx directly through the channel. [8]

Once activated the ASIC can go on to trigger multitudes of different effector proteins and signaling molecules to result in different reactions from the cell. Namely, α-Actinin results in heightened pH sensitivity and desensitization recovery. They can also increase current flow density through the channel. [8] There are also many protein kinases that regulate ASIC function through phosphorylation. These include protein kinase A (PKA) and protein kinase C (PKC). There are thought to be many more regulators, yet their effects have not been experimentally concluded. [8]

There are some other factors that can play a role on the regulation of the ASICs. The presence of matured N-linked glycans on the surface of the channel is said to allow the channel to preferentially traffic for ASIC1a. This is a result from the increased N-glycosylation sites on ASIC1a and ASIC2a. [8] The high levels of glycerol (known to expedite protein maturation) on ASIC2 surface also aids in the implication that regulation of these channels' function is reliant on protein maturation. It is also hypothesized that oxidation plays a role in trafficking. [8]

Location

Most ASIC are expressed in the nervous system. ASIC1, ASIC2, ASIC2b, and ASIC4 are commonly expressed in both the central and peripheral nervous system, while ASIC1b and ASIC3 are typically only located in the peripheral.

In the peripheral nervous system, ASICs are located within the cell bodies of postsynaptic membranes and sensory nerve terminals. Additionally, ASICs are typically found in afferent nerve fibers of the skin, muscles, joints, and viscera, where they have been discovered to be associated with pain, taste, and gastrointestinal functions. [6]

In the central nervous system ASIC's are usually found in the dorsal horn of the spinal cord. [4] ASIC1 is specifically concentrated in the amygdala, illustrating its role in anxious behavior and ASIC3 has been found in the organ of Corti and spiral ganglion illustrating this specific channel's role in auditory and vision perception. [6] Subunits ASIC1a, ASIC2a and ASIC2b have also been found in the hippocampus. [9]

Physiology

ASICs are potential drug targets for treating a wide variety of conditions linked to both the CNS and PNS. [4] [5] Of particular interest to pain field is the ASIC3 subtype receptor, which is specifically expressed in nociceptors. This subtype exhibits a biphasic current upon proton activation, where the initial inward Na+ current is shortly followed by a sustained cationic current.

ASICs are important in retinal function and offer protection in response to bright light. The susceptibility of retinal damage is increased after deletion of the ASIC2 gene. Increased apoptosis occurred in response to bright light in an ASIC2 -/- gene compared to wild type retina. [8]

ASIC1a channels also play a role in protection against seizure activity. Seizures cause increased, uncontrolled neuronal activity in the brain that releases large quantities of acidic vesicles. [5] ASIC1a channels open in response and have shown to protect against seizures by reducing their progression. Studies researching this phenomenon have found that deleting the ASIC1a gene resulted in amplified seizure activity. [8]

ASIC1a channels specifically open in response to pH 5.0-6.9 and contribute to the pathology of ischemic brain injury because their activation causes a small increase in Ca2+permeability and an inward flow of Ca2+. ASIC1a channels additionally facilitate the activation of voltage-gated Ca2+ channels and NMDA receptor channels upon initial depolarization, contributing to the major increase in intracellular calcium that results in cell death. [10] A possible mechanism of ASIC1a channel-mediated cell death is due to the activation of other channels, leading to elevated Ca2+ which creates signaling pathways for apoptosis and necrosis in the cell. [5] Gene knockout studies as well as ASIC blockades have shown to reduce brain infarct volume by as much as 60%, suggesting ASIC channels play a major role in the development of the pathological states resulting from acidosis and ischemia induced neuronal injury. [10] The effects of both ASIC and NMDA blockades have been studied to determine the roles of both channels in Ca2+ toxicity and assess their respective contributions. The use of blockade for both channels provides greater neuroprotection than using a blockade for just one channel, and the ASIC blockade creates prolonged effectiveness of the NMDA blockade. [10]

Pharmacology

Due to the role of acid sensing ion channels in pain perception and several pathophysiological processes, they have a pharmacological significance as a drug target for inhibition. Acid sensing ion channels are found in both central and peripheral neurons. Modulation of ASIC activity may additionally control the adverse behavioral and emotional symptoms of chronic pain such as anxiety and depression.

Acid sensing ion channels (ASIC) are observed to be activated at pH's under ~6 with variability depending on the type of channel and its location. A decrease in pH may be due to a variety of reasons including tissue inflammation, ischemic stroke, an accumulation of lactic acid due to increased cellular metabolism. Activation of the channel causes increased permeability of sodium ions which depolarizes the cell and induces the firing of an action potential. The resulting action potentials may be modulated through small molecule inhibitors.

Amiloride is an example of an ASIC inhibitor, while not considered highly potent due to an IC50 value in the micromolar range, has allowed for studies on ASIC inhibition effects on migraines. During a migraine, cortical spreading depression is observed which causes ion imbalances and the release of charged molecules which may activate ASIC. Testing of amiloride in rodents, showed a decrease in the cortical spreading depression during a migraine. Studies showed that amiloride acts as a competitive inhibitor of the ASIC chapters. The use of amiloride also showed side effects in rodents due to inhibition of sodium/ calcium exchangers. The inhibition of these exchangers disrupts cellular calcium homeostasis and causes high levels of calcium in the cell which explains the reduced neuroprotective efficacy with the use of amiloride. The findings that have come through due to ASIC inhibition by amiloride are promising and support the therapeutic potential. However, due to amiloride's lack of specificity and potency, further drug development on its structure will need to be done before a drug can be released. [11] [10]

A small molecule inhibitor, A-317567, shows more therapeutic potential than amiloride with a higher specificity to ASIC channels and increased potency. Although A-317567 shows little selectivity for the different kinds of ASIC channels, in vivo findings showed that the side-effects seen with amiloride use are avoided due to A-317567's specificity for ASIC. Additionally, A-317567 has the ability to maintain inhibition of sustained currents which could be promising specifically in acidosis-mediated chronic conditions. [10]

The most effective and best-known inhibitor of ASICs is PcTX1. PcTX1 specifically inhibits ASICa and has an IC50 value in the nanomolar range- a smaller IC50 than all other known ASIC inhibitors which have been in the micromolar range. In addition, PcTX1 does not inhibit other voltage-gated ion channels or ligand-gated channels. The structure of this inhibitor is 40 amino acids linked with disulfide bonds. It was identified as a peptide toxin from the South American tarantula Psalmopoeus Cambridge . [10] When PcTX1 was administered within the basolateral amygdala of rats, the emotion and anxiety related symptoms associated with pain were significantly decreased. [12] Mambalgins isolated from the venom of the black mamba have also been identified as potent inhibitors of ASICs. [13]

Commonly used non-steroid anti-inflammatory drugs (NSAIDs) have been found to play a role in ASIC inhibition which contributes to pain modulation. The well-known mechanism for NSAID function is their inhibition of prostaglandin synthesis, a major inflammatory compound. However, findings show that NSAIDs ibuprofen and aspirin inhibit ASICs with IC50 values of 350μM and 260μM, respectively. NSAIDs likely inhibit the ASIC current during acute pain, particularly that caused by tissue inflammation, and thus inhibit the signal to pain-sensing neurons. [10]

By furthering research on the pharmacological potential in ASIC inhibition, patients suffering with chronic pain and various pathologies associated with acidosis may have greater treatment options in the future. Additionally, drug discovery studies of ASICs provide greater knowledge on the function of the channels themselves and their physiological significance.

Related Research Articles

<span class="mw-page-title-main">BK channel</span> Family of transport proteins

BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca2+ concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels.

<span class="mw-page-title-main">Voltage-gated ion channel</span> Type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in a cell's electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

<span class="mw-page-title-main">Chloride channel</span> Class of transport proteins

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.

<span class="mw-page-title-main">G protein-gated ion channel</span>

G protein-gated ion channels are a family of transmembrane ion channels in neurons and atrial myocytes that are directly gated by G proteins.

<span class="mw-page-title-main">Sodium channel</span> Transmembrane protein allowing sodium ions in and out

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.

<span class="mw-page-title-main">P2X purinoreceptor</span>

The P2X receptors, also ATP-gated P2X receptor cation channel family, is a protein family that consists of cation-permeable ligand-gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors known as the ENaC/P2X superfamily. ENaC and P2X receptors have similar 3-D structures and are homologous. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.

<span class="mw-page-title-main">Epithelial sodium channel</span> Group of membrane proteins

The epithelial sodium channel(ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (Na+). It is assembled as a heterotrimer composed of three homologous subunits α or δ, β, and γ, These subunits are encoded by four genes: SCNN1A, SCNN1B, SCNN1G, and SCNN1D. The ENaC is involved primarily in the reabsorption of sodium ions at the collecting ducts of the kidney's nephrons. In addition to being implicated in diseases where fluid balance across epithelial membranes is perturbed, including pulmonary edema, cystic fibrosis, COPD and COVID-19, proteolyzed forms of ENaC function as the human salt taste receptor.

Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct sodium ions, calcium ions and possibly hydrogen ions. Plant TPC1s are non-selective channels. Expression of TPCs are found in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and lysosomes. TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. Quasi-tetramers appear very similar to tetramers, but are not quite the same. Some key roles of TPCs include calcium dependent responses in muscle contraction(s), hormone secretion, fertilization, and differentiation. Disorders linked to TPCs include membrane trafficking, Parkinson's disease, Ebola, and fatty liver.

<span class="mw-page-title-main">SK channel</span> Protein subfamily of calcium-activated potassium channels

SK channels are a subfamily of calcium-activated potassium channels. They are so called because of their small single channel conductance in the order of 10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated (opened) by an increase in the concentration of intracellular calcium through N-type calcium channels. Their activation limits the firing frequency of action potentials and is important for regulating afterhyperpolarization in the neurons of the central nervous system as well as many other types of electrically excitable cells. This is accomplished through the hyperpolarizing leak of positively charged potassium ions along their concentration gradient into the extracellular space. This hyperpolarization causes the membrane potential to become more negative. SK channels are thought to be involved in synaptic plasticity and therefore play important roles in learning and memory.

<span class="mw-page-title-main">N-type calcium channel</span> Protein family

N-type calcium channels also called Cav2.2 channels are voltage gated calcium channels that are localized primarily on the nerve terminals and dendrites as well as neuroendocrine cells. The calcium N-channel consists of several subunits: the primary subunit α1B and the auxiliary subunits α2δ and β. The α1B subunit forms the pore through which the calcium enters and helps to determine most of the channel's properties. These channels play an important role in the neurotransmission during development. In the adult nervous system, N-type calcium channels are critically involved in the release of neurotransmitters, and in pain pathways. N-type calcium channels are the target of ziconotide, the drug prescribed to relieve intractable cancer pain. There are many known N-type calcium channel blockers that function to inhibit channel activity, although the most notable blockers are ω-conotoxins.

<span class="mw-page-title-main">L-type calcium channel</span> Family of transport proteins

The L-type calcium channel is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This channel has four isoforms: Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

<span class="mw-page-title-main">ASIC1</span> Protein-coding gene in humans

Acid-sensing ion channel 1 (ASIC1) also known as amiloride-sensitive cation channel 2, neuronal (ACCN2) or brain sodium channel 2 (BNaC2) is a protein that in humans is encoded by the ASIC1 gene. The ASIC1 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 1996. The ASIC genes have splicing variants that encode different proteins that are called isoforms.

<span class="mw-page-title-main">ASIC3</span> Protein-coding gene in the species Homo sapiens

Acid-sensing ion channel 3 (ASIC3) also known as amiloride-sensitive cation channel 3 (ACCN3) or testis sodium channel 1 (TNaC1) is a protein that in humans is encoded by the ASIC3 gene. The ASIC3 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 1998. The ASIC genes have splicing variants that encode different proteins that are called isoforms.

<span class="mw-page-title-main">ASIC2</span> Protein-coding gene in the species Homo sapiens

Acid-sensing ion channel 2 (ASIC2) also known as amiloride-sensitive cation channel 1, neuronal (ACCN1) or brain sodium channel 1 (BNaC1) is a protein that in humans is encoded by the ASIC2 gene. The ASIC2 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 1996. The ASIC genes have splicing variants that encode different proteins that are called isoforms.

<span class="mw-page-title-main">SCNN1D</span> Protein-coding gene in the species Homo sapiens

The SCNN1D gene encodes for the δ (delta) subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1G.

<span class="mw-page-title-main">Psalmotoxin</span>

Psalmotoxin (PcTx1) is a spider toxin from the venom of the Trinidad tarantula Psalmopoeus cambridgei. It selectively blocks Acid Sensing Ion Channel 1-a (ASIC1a), which is a proton-gated sodium channel.

<span class="mw-page-title-main">ASIC4</span> Protein-coding gene in the species Homo sapiens

Acid-sensing ion channel 4 (ASIC4) also known as amiloride-sensitive cation channel 4 (ACCN4) is a protein that in humans is encoded by the ASIC4 gene. The ASIC4 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 2000. The ASIC genes have splicing variants that encode different proteins that are called isoforms.

ASIC5 gene is one of the five paralogous genes that encode proteins that form trimeric Acid-sensing ion channels (ASICs) in mammals. Aliases previously used for this gene include ACCN5 and BASIC. The protein encoded by this gene does not appear to be acid responsive. The cDNA coding for this protein was first characterized in 2000. The ASIC genes have splicing variants that encode different proteins that are called isoforms.

References

  1. ↑ Jasti J, Furukawa H, Gonzales EB, Gouaux E (2007). "Structure of acid-sensing ion channel 1 at 1.9 Å resolution and low pH". Nature. 449 (7160): 316–322. Bibcode:2007Natur.449..316J. doi:10.1038/nature06163. PMID   17882215.
  2. 1 2 Gründer S, Pusch M (July 2015). "Biophysical properties of acid-sensing ion channels (ASICs)". Neuropharmacology. 94: 9–18. doi:10.1016/j.neuropharm.2014.12.016. PMID   25585135. S2CID   34111346.
  3. 1 2 3 4 5 6 7 8 9 10 11 Hanukoglu I (February 2017). "ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters". The FEBS Journal. 284 (4): 525–545. doi:10.1111/febs.13840. PMID   27580245. S2CID   24402104.
  4. 1 2 3 Sluka KA, Winter OC, Wemmie JA (September 2009). "Acid-sensing ion channels: A new target for pain and CNS diseases". Current Opinion in Drug Discovery & Development. 12 (5): 693–704. PMC   3494879 . PMID   19736627.
  5. 1 2 3 4 Wang YZ, Xu TL (December 2011). "Acidosis, acid-sensing ion channels, and neuronal cell death". Molecular Neurobiology. 44 (3): 350–8. doi:10.1007/s12035-011-8204-2. PMID   21932071. S2CID   15169653.
  6. 1 2 3 Osmakov DI, Andreev YA, Kozlov SA (2014). "Acid-sensing ion channels and their modulators". Biochemistry. Biokhimiia. 79 (13): 1528–45. doi:10.1134/S0006297914130069. PMID   25749163. S2CID   14874830.
  7. ↑ Sherwood TW, Frey EN, Askwith CC (October 2012). "Structure and activity of the acid-sensing ion channels". American Journal of Physiology. Cell Physiology. 303 (7): C699–710. doi:10.1152/ajpcell.00188.2012. PMC   3469599 . PMID   22843794.
  8. 1 2 3 4 5 6 7 8 Zha XM (January 2013). "Acid-sensing ion channels: trafficking and synaptic function". Molecular Brain. 6: 1. doi: 10.1186/1756-6606-6-1 . PMC   3562204 . PMID   23281934.
  9. ↑ Baron, A.; Waldmann, R.; Lazdunski, M. (2002). "ASIC-like, proton-activated currents in rat hippocampal neurons. The Journal of Physiology, 539(2), 485–494 | 10.1113/jphysiol.2001.014837". The Journal of Physiology. 539 (Pt 2): 485–494. doi:10.1113/jphysiol.2001.014837. PMC   2290154 . PMID   11882680.
  10. 1 2 3 4 5 6 7 Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP (February 2008). "Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases". Current Opinion in Pharmacology. Neurosciences. 8 (1): 25–32. doi:10.1016/j.coph.2007.09.001. PMC   2267925 . PMID   17945532.
  11. ↑ Baron A, Lingueglia E (July 2015). "Pharmacology of acid-sensing ion channels - Physiological and therapeutical perspectives" (PDF). Neuropharmacology. Acid-Sensing Ion Channels in the Nervous System. 94: 19–35. doi:10.1016/j.neuropharm.2015.01.005. PMID   25613302. S2CID   25550294.
  12. ↑ Aissouni, Youssef; El Guerrab, Abderrahim; Hamieh, Al Mahdy; Ferrier, Jérémy; Chalus, Maryse; Lemaire, Diane; Grégoire, Stéphanie; Etienne, Monique; Eschalier, Alain (2017-03-02). "Acid-Sensing Ion Channel 1a in the amygdala is involved in pain and anxiety-related behaviours associated with arthritis". Scientific Reports. 7: 43617. Bibcode:2017NatSR...743617A. doi:10.1038/srep43617. ISSN   2045-2322. PMC   5340794 . PMID   28321113.
  13. ↑ Diochot S, Baron A, Salinas M, Douguet D, Scarzello S, Dabert-Gay AS, et al. (October 2012). "Black mamba venom peptides target acid-sensing ion channels to abolish pain" (PDF). Nature. 490 (7421): 552–5. Bibcode:2012Natur.490..552D. doi:10.1038/nature11494. PMID   23034652. S2CID   4337253.
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