Molecular Cloning and Regional Distribution of a Human Proton Receptor Subunit with Biphasic Functional Properties

Babinski, K.; Lê, Khanh-Tuoc; Séguéla, Philippe

doi:10.1046/j.1471-4159.1999.0720051.x

Cited by 165 publications

(117 citation statements)

References 30 publications

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“…These, too, have unique N termini and share the C-terminal amino acids (11). Splice variants have not yet been identified for ASIC3 (DRASIC) (12,13) and ASIC4 (SPASIC) (14,15). Except for ASIC2b and ASIC4, all subunits have the ability to form functional homomeric channels when expressed in Xenopus laevis oocytes or mammalian cells.…”

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confidence: 99%

pH Dependency and Desensitization Kinetics of Heterologously Expressed Combinations of Acid-sensing Ion Channel Subunits

Hesselager

Timmermann

Ahring

2004

Journal of Biological Chemistry

297

347

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The exact subunit combinations of functional native acid-sensing ion channels (ASICs) have not been established yet, but both homomeric and heteromeric channels are likely to exist. To determine the ability of different subunits to assemble into heteromeric channels, a number of ASIC1a-, ASIC1b-, ASIC2a-, ASIC2b-, and ASIC3-containing homo-and heteromeric channels were studied by whole-cell patch clamp recordings with respect to pH sensitivity, desensitization kinetics, and level of sustained current normalized to peak current. Analyzing and comparing data for these three features demonstrated unique heteromeric channels in a number of co-expression experiments. Formation of heteromeric ASIC1a؉2a and ASIC1b؉2a channels was foremost supported by the desensitization characteristics that were independent of proton concentration, a feature none of the respective homomeric channels has. Several lines of evidence supported formation of ASIC1a؉3, ASIC1b؉3, and ASIC2a؉3 heteromeric channels. The most compelling was the desensitization characteristics, which, besides being proton-independent, were faster than those of any of the respective homomeric channels. ASIC2b, which homomerically expressed is not activated by protons per se, did not appear to form unique heteromeric combinations with other subunits and in fact appeared to suppress the function of ASIC1b. Co-expression of three subunits such as ASIC1a؉2a؉3 and ASIC1b؉2a؉3 resulted in data that could best be explained by coexistence of multiple channel populations within the same cell. This observation seems to be in good agreement with the fact that ASIC-expressing sensory neurons display a variety of acid-evoked currents.It is well established that tissue acidification, which may be present in inflammatory and ischemic conditions, causes pain (1-3). In line with this, peripheral sensory neurons exhibit sensitivity toward acid by activating several types of depolarizing currents (4 -6). Although the repertoire of ion channels responsible for these currents is not fully known, the family of acid-sensing ion channels (ASICs) 1 is believed to be an important constituent. The ASIC family is a member of the ENaC/ DEG superfamily, which also includes the amiloride-sensitive epithelial sodium channels (ENaCs), the mechanically gated degenerins of Caenorhabditis elegans (DEGs), and a neuropeptide-gated channel of Helix aspersa (FaNaC). The membrane topology of all channels within this superfamily comprises two transmembrane domains, intracellular N and C termini and a large extracellular loop with a number of conserved cysteine residues (7). Currently, four genes encoding six ASIC transcripts have been cloned and characterized from mammalian organisms. ASIC1a (BNaC2) and ASIC1b (ASIC1␤) are the products of alternatively spliced transcripts of the ASIC1 gene that differ in the N-terminal region, including the first transmembrane domain and the proximal part of the large extracellular domain (8 -10). ASIC2a (BNaC1, MDEG) and ASIC2b (MDEG2) are alternatively spliced forms of ...

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confidence: 99%

pH Dependency and Desensitization Kinetics of Heterologously Expressed Combinations of Acid-sensing Ion Channel Subunits

Hesselager

Timmermann

Ahring

2004

Journal of Biological Chemistry

297

347

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“…The ASICs belong to a superfamily that includes amiloride-sensitive epithelial Na ϩ channels (13,14), the FMRFamide-gated Na ϩ channel (15), and the nematode degenerins (DEGs), which probably correspond to mechano-sensitive Na ϩ -permeable channels (16). Several ASIC subunits have now been described: ASIC1a (12), ASIC1b (17), ASIC2a (18 -21), ASIC2b (22), and ASIC3 (23)(24)(25). The different subunits produce channels with different kinetics, external pH sensitivities, and tissue distribution.…”

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confidence: 99%

Isolation of a Tarantula Toxin Specific for a Class of Proton-gated Na+ Channels

Escoubas¹,

Weille²,

Lecoq³

et al. 2000

Journal of Biological Chemistry

439

454

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Acid sensing is associated with nociception, taste transduction, and perception of extracellular pH fluctuations in the brain. Acid sensing is carried out by the simplest class of ligand-gated channels, the family of H ؉ -gated Na ؉ channels. These channels have recently been cloned and belong to the acid-sensitive ion channel (ASIC) family. Toxins from animal venoms have been essential for studies of voltage-sensitive and ligandgated ion channels. This paper describes a novel 40-amino acid toxin from tarantula venom, which potently blocks (IC 50 ‫؍‬ 0.9 nM) a particular subclass of ASIC channels that are highly expressed in both central nervous system neurons and sensory neurons from dorsal root ganglia. This channel type has properties identical to those described for the homomultimeric assembly of ASIC1a. Homomultimeric assemblies of other members of the ASIC family and heteromultimeric assemblies of ASIC1a with other ASIC subunits are insensitive to the toxin. The new toxin is the first high affinity and highly selective pharmacological agent for this novel class of ionic channels. It will be important for future studies of their physiological and physio-pathological roles.Proton-gated Na ϩ -permeable channels are the simplest form of ligand-gated channels. They are present in many neuronal cell types throughout the central nervous system (1-5), suggesting an important function of these channels in signal transduction associated with local pH variations during normal neuronal activity. These channels might also play an important role in pathological situations such as brain ischemia or epilepsy, which produce significant extracellular acidification. They are also present in nociceptive neurons (1-3, 5, 6) and are thought to be responsible for the sensation of pain that accompanies tissue acidosis in muscle and cardiac ischemia (7,8), corneal injury (9), and inflammation and local infection (10, 11). It is only very recently that the first proton-gated channel, acid-sensitive ion channel (ASIC) 1 was cloned (12). The ASICs belong to a superfamily that includes amiloride-sensitive epithelial Na ϩ channels (13, 14), the FMRFamide-gated Na ϩ channel (15), and the nematode degenerins (DEGs), which probably correspond to mechano-sensitive Na ϩ -permeable channels (16). Several ASIC subunits have now been described: ASIC1a (12), ASIC1b (17), ASIC2a (18 -21), ASIC2b (22), and ASIC3 (23-25). The different subunits produce channels with different kinetics, external pH sensitivities, and tissue distribution. They can form functional homomultimers as well as heteromultimers (21,22,26). ASIC1a and ASIC1b both mediate rapidly inactivating currents following rapid and modest acidification of the external pH. However, although ASIC1a is present in both brain and afferent sensory neurons, its splice variant ASIC1b is found only in sensory neurons (17). ASIC2a forms an active H ϩ -gated channel and is abundant in the brain but essentially absent in sensory neurons, whereas its splice variant ASIC2b is present in both brain an...

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“…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).…”

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confidence: 99%

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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Molecular Cloning and Regional Distribution of a Human Proton Receptor Subunit with Biphasic Functional Properties

Cited by 165 publications

References 30 publications

pH Dependency and Desensitization Kinetics of Heterologously Expressed Combinations of Acid-sensing Ion Channel Subunits

pH Dependency and Desensitization Kinetics of Heterologously Expressed Combinations of Acid-sensing Ion Channel Subunits

Isolation of a Tarantula Toxin Specific for a Class of Proton-gated Na+ Channels

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

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