Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system

Rosa, Diego Álvarez de la; Krueger, Stefan; Kolar, Annette; Shao, Dongguo; Fitzsimonds, Reiko Maki; Canessa, Cecilia M.

doi:10.1113/jphysiol.2002.030692

Cited by 183 publications

(138 citation statements)

References 29 publications

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“…6). Immunohistochemical methods also have shown that the ASIC1 subtype is the predominant subtype in the hippocampus and the midbrain (29). These cumulative data support that ASIC1s are also ammonium-gated channels.…”

Section: Discussionsupporting

confidence: 59%

Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage

Pidoplichko

Dani

2006

Proc. Natl. Acad. Sci. U.S.A.

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Acid-sensitive ion channels (ASICs) are proton-gated and belong to the family of degenerin channels. In the mammalian nervous system, ASICs are most well known in sensory neurons, where they are involved in nociception, occurring when injury or inflammation causes acidification. ASICs also are widely expressed in the CNS, and some synaptic roles have been revealed. Because neuronal activity can produce pH changes, ASICs may respond to local acidic transients and alter the excitability of neuronal circuits more widely than is presently appreciated. Furthermore, ASICs have been found to underlie calcium transients that contribute to neuronal death. Degeneration of midbrain dopamine neurons is characteristic of advanced idiopathic Parkinson's disease. Therefore, we tested for functional ASICs in midbrain dopamine neurons of the ventral tegmental area and substantia nigra compacta. Patch-clamp electrophysiology applied to murine midbrain slices revealed abundant acid-sensitive channels. The ASICs were gated and desensitized by extracellular application of millimolar concentrations of NH 4Cl. Although the NH4Cl solution contains micromolar concentrations of NH3 at pH 7.4, our evidence indicates that NH 4 ؉ gates the ASICs. The proton-gated and the ammonium-gated currents were inhibited by tarantula venom (psalmotoxin), which is specific for the ASIC1a subtype. The results show that acidsensitive channels are expressed in midbrain dopamine neurons and suggest that ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus. The ammonium sensitivity suggests a role for ASIC1s in hepatic encephalopathy, cirrhosis, and other neuronal disorders that are associated with hyperammonemia.hepatic encephalopathy ͉ mesolimbic dopamine ͉ Parkinson's disease ͉ proton gating ͉ cirrhosis P roton-gated channels or acid-sensitive ion channels (ASICs) are present in sensory neurons, where they have roles in nociception, taste, and possibly other modalities (1-5). Recently, six ASIC subunits were cloned (6, 7) and identified as belonging to a broad family of degenerin (Deg) channels. ASIC1a (also known as BNaC2) and ASIC1b (ASIC1␤) are the splice variants of the ASIC1 gene (6,8,9). ASIC2a (BNaC1, MDEG) and ASIC2b (MDEG2) are the spliced forms of the ASIC2 gene (10). Other subunits are ASIC3 (DRASIC) (7, 11) and ASIC4 (SPA-SIC) (12, 13). The ASIC subunits form a variety of heteromeric channels in heterologous expression systems, and subunits other than ASIC2b and ASIC4 also form functional homomeric channels in expression systems (14).Although there has been much progress, there is still uncertainty about the pharmacology, the endogenous subunit composition, and the functional significance of different CNS ASIC subtypes (4,5,15,16). ASIC1 is the subunit most abundantly expressed in the mammalian brain and has been shown to be involved in synaptic plasticity (17). ASICs in the CNS also have been implicated in Ca 2ϩ toxicity arising from ischemia, and inhibition or knockout of ASIC1 protected the ...

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Section: Discussionsupporting

confidence: 59%

Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage

Pidoplichko

Dani

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…The staining for ASIC1 and ASIC2 is similar in neurons, slightly punctate and of higher intensity over the soma than on dendrites or axons as observed previously. 18,19 ASIC1 and ASIC2 are enriched in neurons staining positive for the neuronal marker, NeuN. Motoneurons are discerned by their larger size and distinctive multipolar morphology.…”

Section: Resultsmentioning

confidence: 99%

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

et al. 2013

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca 2 þ 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. Cell Death and Differentiation (2013) 20, 589-598; doi:10.1038/cdd.2012.158; published online 11 January 2013Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition where motoneurons in the spinal cord and brain stem die, resulting in paralysis and eventual death. Despite the significant recent advances in understanding the pathophysiology and genetics of ALS, 1 there is no cure for this condition. Currently, the only FDA-approved, disease-modifying drug used for the treatment of ALS is riluzole, which inhibits neuronal glutamate, releases and stimulates glutamate uptake into astrocytes. 2 The use of riluzole is based on the hypothesis that overactivation of Ca 2 þ -permeable AMPA receptors in motoneurons results in excitotoxicity, and that this process contributes to motoneuron death in ALS. 3 Nevertheless, the disease-modifying effects of riluzole therapy are moderate and vary among patients. 4 Acid-sensing ion channels (ASICs) represent a group of ion channels activated by protons. They belong to the epithelial sodium (Na þ ) family of amiloride-sensitive cation channels, and allow for Na þ and Ca 2 þ entry into neurons. Of the six ASIC subunits cloned, ASIC1a, ASIC2a and ASIC2b are expressed in the brain and spinal cord neurons. 5 ASIC1a and ASIC2s are found in the brain regions with high synaptic density and facilitate excitatory synaptic transmission. 6,7 ASIC1a in particular is involved in nociception and fear behavior triggered by hypercapnia. 8,9 ASICs have also been investigated as new targets for the treatment of ischemic stroke and cerebral hypoxia 10 on the premise that activation of ASIC1a during ischemia ...

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“…In agreement with this, experiments showing the contribution of ASIC1a to mGlu-LTD have been observed only in early adult mice, a time in which a post-synaptic mechanism of expression of mGlu-LTD in mature spines has been suggested [40]. On the other hand, immature spines which lack ASICs [41], typically express a pre-synaptic form of LTD [40].…”

Section: Discussionsupporting

confidence: 54%

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus

Mango

Braksator

Battaglia

et al. 2017

Pharmacological Research

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a b s t r a c tAcid-sensing ion channels (ASICs), members of the degenerin/epithelial Na + channel superfamily, are widely distributed in the mammalian nervous system. ASIC1a is highly permeable to Ca 2+ and are thought to be important in a variety of physiological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a in synaptic transmission and plasticity, we investigated metabotropic glutamate (mGlu) receptor-dependent long-term depression (LTD) in the hippocampus. We found that ASIC1a channels mediate a component of LTD in P30-40 animals, since the ASIC1a selective blocker psalmotoxin-1 (PcTx1) reduced the magnitude of LTD induced by application of the group I mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or induced by paired-pulse low frequency stimulation (PP-LFS). Conversely, PcTx1 did not affect LTD in P13-18 animals. We also provide evidence that ASIC1a is involved in group I mGlu receptor-induced increase in action potential firing. However, blockade of ASIC1a did not affect DHPG-induced polyphosphoinositide hydrolysis, suggesting the involvement of some other molecular partners in the functional crosstalk between ASIC1a and group I mGlu receptors. Notably, PcTx1 was able to prevent the increase in GluA1 S845 phosphorylation at the post-synaptic membrane induced by group I mGlu receptor activation. These findings suggest a novel function of ASIC1a channels in the regulation of group I mGlu receptor synaptic plasticity and intrinsic excitability.

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Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system

Cited by 183 publications

References 29 publications

Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage

Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus

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