Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca(2+) overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1(G93A) ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS.

SUBMITTER: Behan AT

PROVIDER: S-EPMC3595486 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Acid-Sensing Ion Channels Contribute to Type III Adenylyl Cyclase-Independent Acid Sensing of Mouse Olfactory Sensory Neurons.

Project description:Acids can disturb the ecosystem of wild animals through altering their olfaction and olfaction-related survival behaviors. It is known that the main olfactory epithelia (MOE) of mammals rely on odorant receptors and type III adenylyl cyclase (AC3) to detect general odorants. However, it is unknown how the olfactory system sense protons or acidic odorants. Here, we show that while the MOE of AC3 knockout (KO) mice failed to respond to an odor mix in electro-olfactogram (EOG) recordings, it retained a small fraction of acid-evoked EOG responses. The acetic acid-induced EOG responses in wild-type (WT) MOE can be dissected into two components: the big component dependent on the AC3-mediated cAMP pathway and the much smaller component not. The small acid-evoked EOG response of the AC3 KOs was blocked by diminazene, an inhibitor of acid-sensing ion channels (ASICs), but not by forskolin/IBMX that desensitize the cAMP pathway. AC3 KO mice lost their sensitivity to detect pungent odorants but maintained sniffing behavior to acetic acid. Immunofluorescence staining demonstrated that ASIC1 proteins were highly expressed in olfactory sensory neurons (OSNs), mostly enriched in the knobs, dendrites, and somata, but not in olfactory cilia. Real-time polymerase chain reaction further detected the mRNA expression of ASIC1a, ASIC2b, and ASIC3 in the MOE. Additionally, mice exhibited reduced preference to attractive objects when placed in an environment with acidic volatiles. Together, we conclude that the mouse olfactory system has a non-conventional, likely ASIC-mediated ionotropic mechanism for acid sensing.

| S-EPMC7398588 | biostudies-literature

Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity.

Project description:Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission.

| S-EPMC4115047 | biostudies-literature

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

Project description: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.

| S-EPMC5146928 | biostudies-literature

Acid-sensing (proton-gated) ion channels (ASICs)

Project description: Not available

| S-EPMC2884552 | biostudies-literature

Gating mechanisms of acid-sensing ion channels.

Project description:Acid-sensing ion channels (ASICs) are trimeric, proton-gated and sodium-selective members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout vertebrate central and peripheral nervous systems. Gating of ASICs occurs on a millisecond time scale and the mechanism involves three conformational states: high pH resting, low pH open and low pH desensitized. Existing X-ray structures of ASIC1a describe the conformations of the open and desensitized states, but the structure of the high pH resting state and detailed mechanisms of the activation and desensitization of the channel have remained elusive. Here we present structures of the high pH resting state of homotrimeric chicken (Gallus gallus) ASIC1a, determined by X-ray crystallography and single particle cryo-electron microscopy, and present a comprehensive molecular mechanism for proton-dependent gating in ASICs. In the resting state, the position of the thumb domain is further from the three-fold molecular axis, thereby expanding the 'acidic pocket' in comparison to the open and desensitized states. Activation therefore involves 'closure' of the thumb into the acidic pocket, expansion of the lower palm domain and an iris-like opening of the channel gate. Furthermore, we demonstrate how the β11-β12 linkers that demarcate the upper and lower palm domains serve as a molecular 'clutch', and undergo a simple rearrangement to permit rapid desensitization.

| S-EPMC5966032 | biostudies-literature

Activating Acid-Sensing Ion Channels with Photoacid Generators.

Project description:Acid-sensing ion channels (ASICs), present in both central and peripheral neurons, respond to changes in extracellular protons. They play important roles in many symptoms and diseases, such as pain, ischemic stroke and neurodegenerative diseases. Herein, we report a novel approach to activate ASICs with the precision of light using organic photoacid generators (PAGs), which are molecules that release H+ upon light illumination, and have been recently used in biomedical studies. The PAGs showed low toxicity in dark conditions. Under LED light illumination, ASICs activation and consequent calcium ion influx was monitored and analysed by fluorescence microscopy, and showed a strong light-dependent response. This approach allows the activation of ASICs with the precision of light, and may be valuable to help better elucidate the molecular mechanism of ASICs and unveil their roles in physiology, pathophysiology, and behaviour.

| S-EPMC9455902 | biostudies-literature

Acid-sensing ion channels interact with and inhibit BK K+ channels.

Project description:Acid-sensing ion channels (ASICs) are neuronal non-voltage-gated cation channels that are activated when extracellular pH falls. They contribute to sensory function and nociception in the peripheral nervous system, and in the brain they contribute to synaptic plasticity and fear responses. Some of the physiologic consequences of disrupting ASIC genes in mice suggested that ASIC channels might modulate neuronal function by mechanisms in addition to their H(+)-evoked opening. Within ASIC channel's large extracellular domain, we identified sequence resembling that in scorpion toxins that inhibit K(+) channels. Therefore, we tested the hypothesis that ASIC channels might inhibit K(+) channel function by coexpressing ASIC1a and the high-conductance Ca(2+)- and voltage-activated K(+) (BK) channel. We found that ASIC1a associated with BK channels and inhibited their current. Reducing extracellular pH disrupted the association and relieved the inhibition. BK channels, in turn, altered the kinetics of ASIC1a current. In addition to BK, ASIC1a inhibited voltage-gated Kv1.3 channels. Other ASIC channels also inhibited BK, although acidosis-dependent relief of inhibition varied. These results reveal a mechanism of ion channel interaction and reciprocal regulation. Finding that a reduced pH activated ASIC1a and relieved BK inhibition suggests that extracellular protons may enhance the activity of channels with opposing effects on membrane voltage. The wide and varied expression patterns of ASICs, BK, and related K(+) channels suggest broad opportunities for this signaling system to alter neuronal function.

| S-EPMC2268598 | biostudies-literature

Ion selectivity in the selectivity filters of acid-sensing ion channels.

Project description:Sodium-selective acid sensing ion channels (ASICs), which belong to the epithelial sodium channel (ENaC) superfamily, are key players in many physiological processes (e.g. nociception, mechanosensation, cognition, and memory) and are potential therapeutic targets. Central to the ASIC's function is its ability to discriminate Na(+) among cations, which is largely determined by its selectivity filter, the narrowest part of an open pore. However, it is unclear how the ASIC discriminates Na(+) from rival cations such as K(+) and Ca(2+) and why its Na(+)/K(+) selectivity is an order of magnitude lower than that of the ENaC. Here, we show that a well-tuned balance between electrostatic and solvation effects controls ion selectivity in the ASIC1a SF. The large, water-filled ASIC1a pore is selective for Na(+) over K(+) because its backbone ligands form more hydrogen-bond contacts and stronger electrostatic interactions with hydrated Na(+) compared to hydrated K(+). It is selective for Na(+) over divalent Ca(2+) due to its relatively high-dielectric environment, which favors solvated rather than filter-bound Ca(2+). However, higher Na(+)-selectivity could be achieved in a narrow, rigid pore lined by three weak metal-ligating groups, as in the case of ENaC, which provides optimal fit and interactions for Na(+) but not for non-native ions.

| S-EPMC4297968 | biostudies-literature

Diarylamidines: high potency inhibitors of acid-sensing ion channels.

Project description:Acid-sensing ion channels (ASICs) are proton-gated cation channels that are predominantly expressed in the nervous system. ASICs are involved in a number of neurological diseases such as pain, ischemic stroke and multiple sclerosis but limited tools are available to target these channels and provide probes for their physiological functions. Here we report that the anti-protozoal diarylamidines, 4',6-diamidino-2-phenylindole (DAPI), diminazene, hydroxystilbamidine (HSB) and pentamidine potently inhibit ASIC currents in primary cultured hippocampal neurons with apparent affinities of 2.8 microM, 0.3 microM, 1.5 microM and 38 microM, respectively. These four compounds (100 microM) failed to block ENaC channels expressed in oocytes. Sub-maximal concentrations of diminazene also strongly accelerated desensitization of ASIC currents in hippocampal neurons. Diminazene blocked ASIC1a, -1b -2a, and -3 currents expressed in CHO cells with a rank order of potency 1b > 3 > 2a >or= 1a. Patchdock computational analysis suggested a binding site of diarylamidines on ASICs. This study indicates diarylamidines constitute a novel class of non-amiloride ASIC blockers and suggests that diarylamidines may be developed as therapeutic agents in treatment of ASIC-involved diseases.

| S-EPMC3846926 | biostudies-literature

Structure and activity of the acid-sensing ion channels.

Project description:The acid-sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of complex behaviors including fear, anxiety, pain, depression, learning, and memory. ASICs have also been implicated in neuronal degeneration accompanying ischemia and multiple sclerosis. As a whole, ASICs represent novel therapeutic targets for several clinically important disorders. An understanding of the correlation between ASIC structure and function will help to elucidate their mechanism of action and identify potential therapeutics that specifically target these ion channels. Despite the seemingly simple nature of proton binding, multiple studies have shown that proton-dependent gating of ASICs is quite complex, leading to activation and desensitization through distinct structural components. This review will focus on the structural aspects of ASIC gating in response to both protons and the newly discovered activators GMQ and MitTx. ASIC modulatory compounds and their action on proton-dependent gating will also be discussed. This review is dedicated to the memory of Dale Benos, who made a substantial contribution to our understanding of ASIC activity.

| S-EPMC3469599 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data