Role Of Acid-sensing Ion Channels Research Articles

The role of acid-sensing ion channels in monosodium urate-induced gouty pain in mice.

Acid-sensing ion channels (ASICs) in dorsal root ganglion (DRG) neurons play an important role in inflammatory pain. The objective of this study is to observe the regulatory role of ASICs in monosodium urate (MSU) crystal-induced gout pain and explore the basis for ASICs in DRG neurons as a target for gout pain treatment. The gout arthritis model was induced by injecting MSU crystals into the ankle joint of mice. The circumference of the ankle joint was used to evaluate the degree of swelling; the von Frey filaments were used to determine the withdrawal threshold of the paw. ASIC currents and action potentials (APs) were recorded by patch clamp technique in DRG neurons. The results displayed that injecting MSU crystals caused ankle edema and mechanical hyperalgesia of the paw, which was relieved after amiloride treatment. The ASIC currents in DRG neurons were increased to a peak on the second day after injecting MSU crystals, which were decreased after amiloride treatment. MSU treatment increased the current density of ASICs in different diameter DRG cells. MSU treatment does not change the characteristics of AP. The results suggest that ASICs in DRG neurons participate in MSU crystal-induced gout pain.

Genetic exploration of roles of acid-sensing ion channel subtypes in neurosensory mechanotransduction including proprioception.

Although acid-sensing ion channels (ASICs) are proton-gated ion channels responsible for sensing tissue acidosis, accumulating evidence has shown that ASICs are also involved in neurosensory mechanotransduction. However, in contrast to Piezo ion channels, evidence of ASICs as mechanically gated ion channels has not been found using conventional mechanoclamp approaches. Instead, ASICs are involved in the tether model of mechanotransduction, with the channels gated via tethering elements of extracellular matrix and intracellular cytoskeletons. Methods using substrate deformation-driven neurite stretch and micropipette-guided ultrasound were developed to reveal the roles of ASIC3 and ASIC1a, respectively. Here we summarize the evidence supporting the roles of ASICs in neurosensory mechanotransduction in knockout mouse models of ASIC subtypes and provide insight to further probe their roles in proprioception.

Acid-Sensing Ion Channels in Glial Cells.

Acid-sensing ion channels (ASICs) are proton-gated cation channels and key mediators of responses to neuronal injury. ASICs exhibit unique patterns of distribution in the brain, with high expression in neurons and low expression in glial cells. While there has been a lot of focus on ASIC in neurons, less is known about the roles of ASICs in glial cells. ASIC1a is expressed in astrocytes and might contribute to synaptic transmission and long-term potentiation. In oligodendrocytes, constitutive activation of ASIC1a participates in demyelinating diseases. ASIC1a, ASIC2a, and ASIC3, found in microglial cells, could mediate the inflammatory response. Under pathological conditions, ASIC dysregulation in glial cells can contribute to disease states. For example, activation of astrocytic ASIC1a may worsen neurodegeneration and glioma staging, activation of microglial ASIC1a and ASIC2a may perpetuate ischemia and inflammation, while oligodendrocytic ASIC1a might be involved in multiple sclerosis. This review concentrates on the unique ASIC components in each of the glial cells and integrates these glial-specific ASICs with their physiological and pathological conditions. Such knowledge provides promising evidence for targeting of ASICs in individual glial cells as a therapeutic strategy for a diverse range of conditions.

Acid-Sensing Ion Channels: Focus on Physiological and Some Pathological Roles in the Brain.

Acid-sensing ion channels (ASICs) are Na+-permeable ion channels activated by protons and predominantly expressed in the nervous system. ASICs act as pH sensors leading to neuronal excitation. At least eight different ASIC subunits (including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, ASIC4, ASIC5) are encoded by five genes (ASIC1-ASIC5). Functional ASICs assembled in the plasma membrane are homo- or heteromeric trimers. ASIC1a-containing trimers are of particular interest as, in addition to sodium ions, they also conduct calcium ions and thus can trigger or regulate multiple cellular processes. ASICs are widely but differentially expressed in the central and peripheral nervous systems. In the mammalian brain, a majority of neurons express at least one ASIC subunit. Several recent reviews have summarized findings of the role of ASICs in the peripheral nervous system, particularly in nociception and proprioception, and the structure-function relationship of ASICs. However, there is little coverage on recent findings regarding the role of ASICs in the brain. Here we review and discuss evidence regarding the roles of ASICs: (i) as postsynaptic receptors activated by protons co-released with glutamate at glutamatergic synapses; (ii) as modulators of synaptic transmission at glutamatergic synapses and GABAergic synapses; (iii) in synaptic plasticity, memory and learning; (iv) in some pathologies such as epilepsy, mood disorders and Alzheimer's disease.

Extracellular Protons Mediate Presynaptic Homeostatic Potentiation at the Mouse Neuromuscular Junction

At the vertebrate neuromuscular junction (NMJ), presynaptic homeostatic potentiation (PHP) refers to the upregulation of neurotransmitter release via an increase in quantal content (QC) when the postsynaptic nicotinic acetylcholine receptors (nAChRs) are partially blocked. The mechanism of PHP has not been completely worked out. In particular, the identity of the presumed retrograde signal is still a mystery. We investigated the role of acid-sensing ion channels (ASICs) and extracellular protons in mediating PHP at the mouse NMJ. We found that blocking AISCs using benzamil, psalmotoxin-1 (PcTx1), or mambalgin-3 (Mamb3) prevented PHP. Likewise, extracellular acidification from pH 7.4 to 7.2 triggered a significant, reversable increase in QC and this increase could be prevented by PcTx1. Interestingly, an acidic saline (pH 7.2) also precluded the subsequent induction of PHP. Using immunofluorescence we observed ASIC2a and ASIC1 subunits at the NMJ. Our results indicate that protons and ASIC channels are involved in activating PHP at the mouse NMJ. We speculate that the partial blockade of nAChRs leads to a modest decrease in the pH of the synaptic cleft (∼0.2 pH units) and this activates ASIC channels on the presynaptic nerve terminal.

Citric Acid in Drug Formulations Causes Pain by Potentiating Acid-Sensing Ion Channel 1.

Pain at the injection site is a common complaint of patients receiving therapeutic formulations containing citric acid. Despite the widely acknowledged role of acid-sensing ion channels (ASICs) in acid-related perception, the specific ASIC subtype mediating pain caused by subcutaneous acid injection and the mechanism by which citrate affects this process are less clear. Here, male mice subjected to intraplantar acid injection responded by executing a withdrawal reflex, and this response was abolished by ASIC1 but not ASIC2 knockout. Although intraplantar injection of neutral citrate solution did not produce this response, intraplantar injection of acidic citrate solution produced a withdrawal reflex greater than that produced by acidity alone. Consistent with the behavioral data, neutral citrate failed to produce an electrophysiological response in HEK293 cells, which express ASIC1, but acidic citrate produced a whole-cell inward current greater than that produced by acidity alone. Saturating the intracellular solution with citrate had no effect on the potentiating effect of extracellular citrate, suggesting that citrate acted extracellularly to potentiate ASIC1. Moreover, exposure to citrate immediately before acid stimulation failed to potentiate ASIC1 currents, which ruled out the involvement of a metabotropic receptor gated by a citrate metabolite. Finally, removal of calcium ions from the extracellular solution mimicked the potentiating effect of citrate and prevented citrate from further potentiating ASIC1. Our data demonstrate that ASIC1 is necessary for the nociceptive response caused by subcutaneous acid infusion and that neutral citrate, despite not inducing ASIC1 currents or nociceptive behavior on its own, potentiates acid nociception by removing the inhibitory effect of extracellular calcium ions on ASIC1.SIGNIFICANCE STATEMENT Citric acid is a common ingredient used in pharmaceutical formulations. Despite the widespread clinical use of these formulations, it remains unclear how citric acid causes pain when injected into patients. We identified ASIC1 as the key receptor used to detect injection-site pain caused by acid, and we showed that neutral citrate does not stimulate ASIC1; instead, citrate substantially potentiates ASIC1 activation when injected simultaneously with acid. In addition, we demonstrated that citrate potentiates ASIC1 by removing the inhibitory action of calcium on the extracellular side of the receptor. Given that injection-site pain is the primary complaint of patients receiving citrate-containing medical products, our data provide mechanistic insight into a common medical complaint and suggest a means of avoiding injection pain.

Role of Acid-sensing Ion Channel 1 in sensing acidification and triggering inflammation in Nasal Polyps with Asthma

A variety of inflammatory cells are infiltrated histologically in sinonasal mucosa of chronic rhinosinusitis with nasal polyps (CRSwNP), especially CRSwNP with asthma. Acid-sensing ion channel 1 (ASIC1) are essential in the process of sensing acidification and triggering inflammation. The present study aimed to explore the roles and mechanism of ASIC1 in the pathogenesis of CRSwNP.

A Novel Role Of ASICs In Immediate Exercise-Induced Pain And Exercise Performance

D-13 Thematic Poster - RPE, Pain and Fatigue Thursday, May 28, 2020, 1:30 PM - 3:30 PM Room: CC-2011 INTRODUCTION: Exercise training is an effective therapy for many pain-related conditions, and there is a difference in pain perception between athletes and unconditioned people. The mechanisms by which exercise modulates pain are poorly understood. Painful conditions can be associated with elevated levels of protons, metabolites and inflammatory factors, which can activate receptors and/or ion channels on nociceptive sensory neurons including acid sensing ion channels (ASICs) and transient receptor potential cation channel subfamily V member 1 (TRPV1). Additionally, strenuous exercise also causes the release of similar chemical signals, and ASICs within muscle afferents may mediate immediate exercise-induced pain (IEP) and fatigue, as well as reflex hemodynamic changes. We hypothesized that ASICs and TRPV1 have role in IEP and maximal exercise performance. METHOD: First, C57BL/6 mice were divided into sedentary (SED), low-intensity continuous training (LICT) and high-intensity interval training (HIIT) groups. Mice were trained on a treadmill every other day for 4 weeks. SED mice were placed on a non-moving treadmill for similar periods of time. After 4 weeks, exercise performance, ASICs and TRPV1 mRNA levels within lumbar dorsal root ganglion (DRG) were measured. In a separate group, we measured IEP at baseline and following exhaustive exercise before and after HIIT. In a third study, we compared the IEP and exercise performance in ASIC3-/- versus wild type (WT) mice. RESULTS: We found HIIT improved exercise performance compared to LICT and sedentary groups, diminished ASICs and TRPV1 mRNA levels in lumber DRG, and reduced IEP. We also found a negative relationship between mRNA levels of ASICs and TRPV1 and exercise performance (r = - 0.59, p < 0.001). In addition, ASIC3-/- showed a significant lower IEP compared to WT mice, while there was no difference in maximal exercise performance between groups. CONCLUSION: In summary, ASIC3 is required for IEP following exhaustive exercise, and exercise training downregulates ASICs and TRPV1 in muscle afferents and diminishes IEP. These findings suggest a possible role of ASICs in benefits of exercise training for many pain and fatigue conditions such as fibromyalgia and chronic fatigue syndrome conditions. Supported by Department of Veteran Affairs.

The Role of Acid-sensing Ion Channel 3 in the Modulation of Tooth Mechanical Hyperalgesia Induced by Orthodontic Tooth Movement

This study aimed to explore the role of acid-sensing ion channel 3 (ASIC3) in the modulation of tooth mechanical hyperalgesia induced by orthodontic tooth movement. In male Sprague-Dawley rats, closed coil springs were ligated between mandibular incisors and molars to mimic orthodontic tooth movement. Bite force was assessed to evaluate tooth mechanical hyperalgesia. The alveolar bone, trigeminal ganglia, and trigeminal nucleus caudalis underwent immunohistochemical staining and immunoblotting for ASIC3. The inferior alveolar nerves were transected to explore the interaction between the periodontal sensory endings and trigeminal ganglia. The role of ASIC3 in trigeminal ganglia was further explored with lentivirus-mediated ASIC3 ribonucleic acid interference. Results showed that ASIC3 was expressed in the periodontal Ruffini endings and expression of ASIC3 protein was elevated in periodontal tissues, trigeminal ganglia, and trigeminal nucleus caudalis, following orthodontic tooth movement. ASIC3 agonists and antagonists significantly aggravated and mitigated tooth mechanical hyperalgesia, respectively. ASIC3 expression decreased after inferior alveolar nerve transection in periodontal tissues. Both in vitro and vivo, the lentivirus vector carrying ASIC3 shRNA inhibited ASIC3 expression and relieved tooth mechanical hyperalgesia. To conclude, ASIC3 is important in the modulation of tooth mechanical hyperalgesia induced by orthodontic tooth movement. Further, the role of ASIC3 in the modulation of pain in periodontal tissues is regulated by trigeminal ganglia. An adjuvant analgesic therapy targeting ASIC3 could alleviate orthodontic movement-associated mechanical hyperalgesia in rats.

Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons.

Acid-sensing ion channels (ASICs) are H+-activated neuronal Na+ channels. They are involved in fear behavior, learning, neurodegeneration after ischemic stroke and in pain sensation. ASIC activation has so far been studied only with fast pH changes, although the pH changes associated with many roles of ASICs are slow. It is currently not known whether slow pH changes can open ASICs at all. Here, we investigated to which extent slow pH changes can activate ASIC1a channels and induce action potential signaling. To this end, ASIC1a current amplitudes and charge transport in transfected Chinese hamster ovary cells, and ASIC-mediated action potential signaling in cultured cortical neurons were measured in response to defined pH ramps of 1–40 s duration from pH 7.4 to pH 6.6 or 6.0. A kinetic model of the ASIC1a current was developed and integrated into the Hodgkin-Huxley action potential model. Interestingly, whereas the ASIC1a current amplitude decreased with slower pH ramps, action potential firing was higher upon intermediate than fast acidification in cortical neurons. Indeed, fast pH changes (<4 s) induced short action potential bursts, while pH changes of intermediate speed (4–10 s) induced longer bursts. Slower pH changes (>10 s) did in many experiments not generate action potentials. Computer simulations corroborated these observations. We provide here the first description of ASIC function in response to defined slow pH changes. Our study shows that ASIC1a currents, and neuronal activity induced by ASIC1a currents, strongly depend on the speed of pH changes. Importantly, with pH changes that take >10 s to complete, ASIC1a activation is inefficient. Therefore, it is likely that currently unknown modulatory mechanisms allow ASIC activity in situations such as ischemia and inflammation.

Epigenetic upregulation of acid-sensing ion channel 1 contributes to gastric hypersensitivity in adult offspring rats with prenatal maternal stress.

Functional dyspepsia is a common functional gastrointestinal disorder. Gastric hypersensitivity (GHS) is a hallmark of this disorder, but the cellular mechanisms remain largely unknown. Stressors during gestational period could have effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of this study was to test whether prenatal maternal stress (PMS) induces GHS and to investigate role of acid-sensing ion channel (ASIC)/nuclear factor-κB (NF-κB) signaling by examining Asic1 methylation status in adult offspring rats. Gastric hypersensitivity in response to gastric distension was examined by electromyography recordings. Changes in neuronal excitability were determined by whole-cell patch-clamp recording techniques. Demethylation of CpG islands of Asic1 was determined by methylation-specific PCR and bisulfite sequencing assay. Prenatal maternal stress produced GHS in adult offspring rats. Treatment with amiloride, an inhibitor of ASICs, significantly attenuated GHS and reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI. Expression of ASIC1 and NF-κBp65 was markedly enhanced in T7 to T10 DRGs. Furthermore, PMS led to a significant demethylation of CpG islands in the Asic1 promoter. A chromatin immunoprecipitation assay showed that PMS also enhanced the ability of NF-κBp65 to bind the promoter of Asic1 gene. Blockade of NF-κB using lentiviral-p65shRNA reversed upregulation of ASIC1 expression, GHS, and the hyperexcitability of DRG neurons. These data suggest that upregulation of ASIC1 expression is attributed to Asic1 promoter DNA demethylation and NF-κB activation, and that the enhanced interaction of the Asic1 and NF-κBp65 contributes to GHS induced by PMS.

ASIC3-dependent metabolomics profiling of serum and urine in a mouse model of fibromyalgia

Fibromyalgia (FM) is characterized by chronic widespread pain. The pathogenesis of FM remains unclear. No specific biomarkers are available. Animal models of FM may provide an opportunity to explore potential biomarkers in a relative homogenous disease condition. Here, we probed the metabolomics profiles of serum and urine in a mouse model of FM induced by intermittent cold stress (ICS). We focused on the role of acid-sensing ion channel 3 (ASIC3) in the metabolomics profiling because ICS treatment induced chronic widespread muscle pain lasting for 1 month in wild-type (Asic3+/+) but not Asic3-knockout (Asic3−/−) mice. Serum and urine samples were collected from both genotypes at different ICS stages, including before ICS (basal level) and post-ICS at days 10 (middle phase, P10) and 40 (recovery phase, P40). Control naïve mice and ICS-induced FM mice differed in 1H-NMR- and LC-MS-based metabolomics profiling. On pathway analysis, the leading regulated pathways in Asic3+/+ mice were taurine and hypotaurine, cysteine and methionine, glycerophospholipid, and ascorbate and aldarate metabolisms, and the major pathways in Asic3−/− mice involved amino acid-related metabolism. Finally, we developed an algorithm for the impactful metabolites in the FM model including cis-aconitate, kynurenate, taurine, pyroglutamic acid, pyrrolidonecarboxylic acid, and 4-methoxyphenylacetic acid in urine as well as carnitine, deoxycholic acid, lysoPC(16:0), lysoPC(20:3), oleoyl-L-carnitine, and trimethylamine N-oxide in serum. Asic3−/− mice were impaired in only muscle allodynia development but not other pain symptoms in the ICS model, so the ASIC3-dependent metabolomics changes could be useful for developing diagnostic biomarkers specific to chronic widespread muscle pain, the core symptom of FM. Further pharmacological validations are needed to validate these metabolomics changes as potential biomarkers for FM diagnosis and/or treatment responses.

Acid-sensing ion channel 1a is involved in ischaemia/reperfusion induced kidney injury by increasing renal epithelia cell apoptosis.

Acidic microenvironment is commonly observed in ischaemic tissue. In the kidney, extracellular pH dropped from 7.4 to 6.5 within 10 minutes initiation of ischaemia. Acid‐sensing ion channels (ASICs) can be activated by pH drops from 7.4 to 7.0 or lower and permeates to Ca2+entrance. Thus, activation of ASIC1a can mediate the intracellular Ca2+ accumulation and play crucial roles in apoptosis of cells. However, the role of ASICs in renal ischaemic injury is unclear. The aim of the present study was to test the hypothesis that ischaemia increases renal epithelia cell apoptosis through ASIC1a‐mediated calcium entry. The results show that ASIC1a distributed in the proximal tubule with higher level in the renal tubule ischaemic injury both in vivo and in vitro. In vivo, Injection of ASIC1a inhibitor PcTx‐1 previous to ischaemia/reperfusion (I/R) operation attenuated renal ischaemic injury. In vitro, HK‐2 cells were pre‐treated with PcTx‐1 before hypoxia, the intracellular concentration of Ca2+, mitochondrial transmembrane potential (∆ψm) and apoptosis was measured. Blocking ASIC1a attenuated I/R induced Ca2+ overflow, loss of ∆ψm and apoptosis in HK‐2 cells. The results revealed that ASIC1a localized in the proximal tubular and contributed to I/R induced kidney injury. Consequently, targeting the ASIC1a may prove to be a novel strategy for AKI patients.

A novel role for acid-sensing ion channels in Pavlovian reward conditioning.

Pavlovian fear conditioning has been shown to depend on acid-sensing ion channel-1A (ASIC1A); however, it is unknown whether conditioning to rewarding stimuli also depends on ASIC1A. Here, we tested the hypothesis that ASIC1A contributes to Pavlovian conditioning to a non-drug reward. We found effects of ASIC1A disruption depended on the relationship between the conditional stimulus (CS) and the unconditional stimulus (US), which was varied between five experiments. In experiment 1, when the CS preceded the US signaling an upcoming reward, Asic1a-/- mice exhibited a deficit in conditioning compared to Asic1a+/+ mice. Alternatively, in experiment 2, when the CS coinitiated with the US and signaled immediate reward availability, the Asic1a-/- mice exhibited an increase in conditioned responses compared to Asic1a+/+ mice, which contrasted with the deficits in the first experiment. Furthermore, in experiments 3 and 4, when the CS partially overlapped in time with the US, or the CS was shortened and coinitiated with the US, the Asic1a-/- mice did not differ from control mice. The contrasting outcomes were likely because of differences in conditioning because in experiment 5 neither the Asic1a-/- nor Asic1a+/+ mice acquired conditioned responses when the CS and US were explicitly unpaired. Taken together, these results suggest that the effects of ASIC1A disruption on reward conditioning depend on the temporal relationship between the CS and US. Furthermore, these results suggest that ASIC1A plays a critical, yet nuanced role in Pavlovian conditioning. More research will be needed to deconstruct the roles of ASIC1A in these fundamental forms of learning and memory.

Inflammasomes in stroke: a triggering role for acid-sensing ion channels.

Stroke is devastating and a major cause of morbidity and mortality around the world. The innate immune response plays an important role in various brain injuries, including stroke, and targeting it for therapeutic interventions would likely prove beneficial. The panoply of inflammatory cells, which induce various cellular, hormonal, and biochemical alterations, mediates the rapid progression of injury in stroke. The inflammasome, a multiprotein oligomer and a key component of specific innate immune responses, contributes toward the worsening of stroke outcomes by activating inflammatory cytokines. Acidotoxicity, mediated by acid-sensing ion channels (ASICs), also contributes toward exacerbating the condition. A role for ASICs in stroke, through the activation of the inflammasome, is emerging, which opens new avenues for understanding and intervening in stroke. In this review, we describe the various types of inflammasomes and their mechanisms of activation in stroke. Furthermore, therapeutic approaches targeting the inflammasome and that may be helpful in improving stroke outcome are discussed.

Role of acid-sensing ion channels in hypoxia- and hypercapnia-induced ventilatory responses.

Previous reports indicate roles for acid-sensing ion channels (ASICs) in both peripheral and central chemoreception, but the contributions of ASICs to ventilatory drive in conscious, unrestrained animals remain largely unknown. We tested the hypotheses that ASICs contribute to hypoxic- and hypercapnic-ventilatory responses. Blood samples taken from conscious, unrestrained mice chronically instrumented with femoral artery catheters were used to assess arterial O2, CO2, and pH levels during exposure to inspired gas mixtures designed to cause isocapnic hypoxemia or hypercapnia. Whole-body plethysmography was used to monitor ventilatory parameters in conscious, unrestrained ASIC1, ASIC2, or ASIC3 knockout (-/-) and wild-type (WT) mice at baseline, during isocapnic hypoxemia and during hypercapnia. Hypercapnia increased respiratory frequency, tidal volume, and minute ventilation in all groups of mice, but there were no differences between ASIC1-/-, ASIC2-/-, or ASIC3-/- and WT. Isocapnic hypoxemia also increased respiratory frequency, tidal volume, and minute ventilation in all groups of mice. Minute ventilation in ASIC2-/- mice during isocapnic hypoxemia was significantly lower compared to WT, but there were no differences in the responses to isocapnic hypoxemia between ASIC1-/- or ASIC3-/- compared to WT. Surprisingly, these findings show that loss of individual ASIC subunits does not substantially alter hypercapnic or hypoxic ventilatory responses.

Roles of ASICs in Nociception and Proprioception.

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.

Acid-sensing ion channels contribute to the effect of extracellular acidosis on proliferation and migration of A549 cells.

Acid-sensing ion channels, a proton-gated cation channel, can be activated by low extracellular pH and involved in pathogenesis of some tumors such as glioma and breast cancer. However, the role of acid-sensing ion channels in the growth of lung cancer cell is unclear. In this study, we investigated the expression of acid-sensing ion channels in human lung cancer cell line A549 and their possible role in proliferation and migration of A549 cells. The results show that acid-sensing ion channel 1, acid-sensing ion channel 2, and acid-sensing ion channel 3 are expressed in A549 cells at the messenger RNA and protein levels, and acid-sensing ion channel-like currents were elicited by extracellular acid stimuli. Moreover, we found that acidic extracellular medium or overexpressing acid-sensing ion channel 1a promotes proliferation and migration of A549 cells. In addition psalmotoxin 1, a specific acid-sensing ion channel 1a inhibitor, or acid-sensing ion channel 1a knockdown can abolish the effect of acid stimuli on A549 cells. In addition, acid-sensing ion channels mediate increase of [Ca2+]i induced by low extracellular pH in A549 cells. All these results indicate that acid-sensing ion channel-calcium signal mediate lung cancer cell proliferation and migration induced by extracellular acidosis, and acid-sensing ion channels may serve as a prognostic marker and a therapeutic target for lung cancer.

Acidity and Acid-Sensing Ion Channels in the Normal and Alzheimer's Disease Brain.

Alzheimer's disease prevalence has reached epidemic proportion with very few treatment options, which are associated with a multitude of side effects. A potential avenue of research for new therapies are protons, and their associated receptor: acid-sensing ion channels (ASIC). Protons are often overlooked neurotransmitters, and proton-gated currents have been identified in the brain. Furthermore, ASICs have been determined to be crucial for proper brain function. While there is more work to be done, this review is intended to highlight protons as neurotransmitters and their role along with the role of ASICs within physiological functioning of the brain. We will also cover the pathophysiological associations between ASICs and modulators of ASICs. Finally, this review will sum up how the studies of protons, ASICs and their modulators may generate new therapeutic molecules for Alzheimer's disease and other neurodegenerative diseases.

Acid-sensing ion channels are expressed in the ventrolateral medulla and contribute to central chemoreception.

The role of acid-sensing ion channels (ASICs) in the ventrolateral medulla (VLM) remains uncertain. Here, we found that ASIC1a and ASIC2 are widely expressed in rat medulla, and the expression level is higher at neonatal stage as compared to adult stage. The two ASIC subunits co-localized in medualla neurons. Furthermore, pH reduction triggered typical ASIC-type currents in the medulla, including the VLM. These currents showed a pH50 value of 6.6 and were blocked by amiloride. Based on their sensitivity to psalmotoxin 1 (PcTx1) and zinc, homomeric ASIC1a and heteromeric ASIC1a/2 channels were likely responsible for acid-mediated currents in the mouse medulla. ASIC currents triggered by pH 5 disappeared in the VLM neurons from ASIC1−/−, but not ASIC2−/− mice. Activation of ASICs in the medulla also triggered neuronal excitation. Moreover, microinjection of artificial cerebrospinal fluid at a pH of 6.5 into the VLM increased integrated phrenic nerve discharge, inspiratory time and respiratory drive in rats. Both amiloride and PcTx1 inhibited the acid-induced stimulating effect on respiration. Collectively, our data suggest that ASICs are highly expressed in the medulla including the VLM, and activation of ASICs in the VLM contributes to central chemoreception.