Target Information

General Information of This Target
Target ID
BTDT00101
Target Name
Acid-sensing ion channel 1 (Asic1)
Target Bioclass
Transporter and channel
Uniprot ID
P55926
3D Structure
Download
2D Sequence
3D Structure
Source
Predict by Alphafold2
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Alphafold Parameters: msa_mode: mmseqs2_uniref_env model_type: auto num_recycles: auto
Gene Name
Asic1
Gene ID
79123
Synonym
Accn2; Bnac2; Amiloride-sensitive cation channel 2, neuronal; Brain sodium channel 2
Sequence
MELKTEEEEVGGVQPVSIQAFASSSTLHGLAHIFSYERLSLKRALWALCFLGSLAVLLCV
CTERVQYYFCYHHVTKLDEVAASQLTFPAVTLCNLNEFRFSQVSKNDLYHAGELLALLNN
RYEIPDTQMADEKQLEILQDKANFRSFKPKPFNMREFYDRAGHDIRDMLLSCHFRGEACS
AEDFKVVFTRYGKCYTFNSGQDGRPRLKTMKGGTGNGLEIMLDIQQDEYLPVWGETDETS
FEAGIKVQIHSQDEPPFIDQLGFGVAPGFQTFVSCQEQRLIYLPSPWGTCNAVTMDSDFF
DSYSITACRIDCETRYLVENCNCRMVHMPGDAPYCTPEQYKECADPALDFLVEKDQEYCV
CEMPCNLTRYGKELSMVKIPSKASAKYLAKKFNKSEQYIGENILVLDIFFEVLNYETIEQ
KKAYEIAGLLGDIGGQMGLFIGASILTVLELFDYAYEVIKHRLCRRGKCQKEAKRSSADK
GVALSLDDVKRHNPCESLRGHPAGMTYAANILPHHPARGTFEDFTC

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Family
the amiloride-sensitive sodium channel family
Function
Proton-gated sodium channel; it is activated by a drop of the extracellular pH and then becomes rapidly desensitized. Generates a biphasic current with a fast inactivating and a slow sustained phase. Has high selectivity for sodium ions and can also transport lithium ions with high efficiency. Can also transport potassium ions, but with lower efficiency. It is nearly impermeable to the larger rubidium and cesium ions. Isoform 3 discrimates stronger than isoform 1 between monovalent cations. Isoform 3 can flux Ca(2+) while isoform 1 cannot. Heteromeric channels composed of isoform 2 and isoform 3 are active but have a lower pH-sensitivity. Mediates glutamate-independent Ca(2+) entry into neurons upon acidosis. This Ca(2+) overloading is toxic for cortical neurons and may be in part responsible for ischemic brain injury. Heteromeric channel assembly seems to modulate channel properties.

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Taxonomy ID
10116
TCDB ID
1.A.6.1.2
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Rodentia
Family: Muridae
Genus: Rattus
Species: Rattus norvegicus
Toxin Information Related to This Target
                           Toxin Name Activity Data Type Activity Data Reference
 Toxin Info    Hi1a Tau(off)
14.2 min
 [1], [2]
 Toxin Info    Kunitz-type neurotoxin MitTx-alpha Effective concentration 50
9.4 nM
 [3], [4]
 Toxin Info    Basic phospholipase A2 homolog MitTx-beta Effective concentration 50
9.4 nM
 [3], [4]
 Toxin Info    Pi-theraphotoxin-Hm3a Effective concentration 50
17.4 nM
 [5]
 Toxin Info    Kunitz-type neurotoxin MitTx-alpha Effective concentration 50
23 nM
 [3], [4]
 Toxin Info    Basic phospholipase A2 homolog MitTx-beta Effective concentration 50
23 nM
 [3], [4]
 Toxin Info    Pi-theraphotoxin-Hm3a Effective concentration 50
46.5 nM
 [5]
 Toxin Info    Kunitz-type neurotoxin MitTx-alpha Effective concentration 50
830 nM
 [3], [4]
 Toxin Info    PcTX1 IC50
0.35 - 3.7 nM
 [1- 20]
 Toxin Info    Hi1a IC50
0.4 nM
 [1], [2]
 Toxin Info    Pi-theraphotoxin-Hm3a IC50
1.3 nM
 [5]
 Toxin Info    Mambalgin-1 IC50
3.4 - 55 nM
 [21- 27]
 Toxin Info    Mambalgin-3 IC50
17 nM
 [22]
 Toxin Info    Mambalgin-2 IC50
21 - 55 nM
 [21- 30]
 Toxin Info    Mambalgin-1 IC50
22.2 - 203 nM
 [21- 27]
 Toxin Info    Mambalgin-3 IC50
44 nM
 [22]
 Toxin Info    Mambalgin-2 IC50
72 nM
 [21- 30]
 Toxin Info    Mambalgin-1 IC50
72 nM
 [21- 27]
 Toxin Info    Pi-phymatoxin-Pcf1a IC50
100 nM
 [31]
 Toxin Info    Mambalgin-2 IC50
103 - 192 nM
 [21- 30]
 Toxin Info    Pi-stichotoxin-Hcr5d IC50
1.25 μM
 [32], [33]
 Toxin Info    Pi/alpha-stichotoxin-Hmg5b IC50
4.8 μM
 [34]
 Toxin Info    Pi-stichotoxin-Hcr5b IC50
4.8 μM
 [32], [33], [35]
 Toxin Info    Pi-stichotoxin-Hcr5c IC50
4.95 μM
 [32], [33]
References
Ref 1 Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3750-3755. doi: 10.1073/pnas.1614728114. Epub 2017 Mar 20.
Ref 2 The antitrypanosomal diarylamidines, diminazene and pentamidine, show anthelmintic activity against Haemonchus contortus in vitro. Vet Parasitol. 2019 Jun;270:40-46. doi: 10.1016/j.vetpar.2019.05.008. Epub 2019 May 19.
Ref 3 A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain. Nature. 2011 Nov 16;479(7373):410-4. doi: 10.1038/nature10607.
Ref 4 X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel. Cell. 2014 Feb 13;156(4):717-29. doi: 10.1016/j.cell.2014.01.011. Epub 2014 Feb 6.
Ref 5 Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1. Neuropharmacology. 2017 Dec;127:185-195. doi: 10.1016/j.neuropharm.2017.03.020. Epub 2017 Mar 19.
Ref 6 Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J Biol Chem. 2000 Aug 18;275(33):25116-21. doi: 10.1074/jbc.M003643200.
Ref 7 The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity. J Gen Physiol. 2005 Jul;126(1):71-9. doi: 10.1085/jgp.200509303. Epub 2005 Jun 13.
Ref 8 Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent. J Gen Physiol. 2006 Mar;127(3):267-76. doi: 10.1085/jgp.200509409. Epub 2006 Feb 14.
Ref 9 Native and recombinant ASIC1a receptors conduct negligible Ca2+ entry. Cell Calcium. 2009 Apr;45(4):319-25. doi: 10.1016/j.ceca.2008.12.002. Epub 2009 Jan 29.
Ref 10 Identification of a calcium permeable human acid-sensing ion channel 1 transcript variant. J Biol Chem. 2010 Dec 31;285(53):41852-62. doi: 10.1074/jbc.M110.171330. Epub 2010 Oct 29.
Ref 11 Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death. J Neurosci. 2011 Jun 29;31(26):9723-34. doi: 10.1523/JNEUROSCI.1665-11.2011.
Ref 12 Protons and Psalmotoxin-1 reveal nonproton ligand stimulatory sites in chicken acid-sensing ion channel: Implication for simultaneous modulation in ASICs. Channels (Austin). 2014;8(1):49-61. doi: 10.4161/chan.26978. Epub 2013 Nov 21.
Ref 13 Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid-sensing ion channel 1a. Br J Pharmacol. 2015 Oct;172(20):4985-95. doi: 10.1111/bph.13267. Epub 2015 Sep 22.
Ref 14 PcTx1 affords neuroprotection in a conscious model of stroke in hypertensive rats via selective inhibition of ASIC1a. Neuropharmacology. 2015 Dec;99:650-7. doi: 10.1016/j.neuropharm.2015.08.040. Epub 2015 Aug 29.
Ref 15 Functional and pharmacological characterization of two different ASIC1a/2a heteromers reveals their sensitivity to the spider toxin PcTx1. Sci Rep. 2016 Jun 9;6:27647. doi: 10.1038/srep27647.
Ref 16 Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms. Neuropharmacology. 2017 Dec;127:173-184. doi: 10.1016/j.neuropharm.2017.04.042. Epub 2017 Apr 27.
Ref 17 Recombinant production and solution structure of PcTx1, the specific peptide inhibitor of ASIC1a proton-gated cation channels. Protein Sci. 2003 Jul;12(7):1332-43. doi: 10.1110/ps.0307003.
Ref 18 A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a. Mol Pharmacol. 2011 Nov;80(5):796-808. doi: 10.1124/mol.111.072207. Epub 2011 Aug 8.
Ref 19 Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes. Nature. 2012 Sep 20;489(7416):400-5. doi: 10.1038/nature11375. Epub 2012 Jul 29.
Ref 20 Structure of the acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1. Nat Commun. 2012 Jul 3;3:936. doi: 10.1038/ncomms1917.
Ref 21 Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature. 2012 Oct 25;490(7421):552-5. doi: 10.1038/nature11494. Epub 2012 Oct 3.
Ref 22 Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels. Toxicon. 2013 Dec 1;75:187-204. doi: 10.1016/j.toxicon.2013.04.008. Epub 2013 Apr 26.
Ref 23 Site-specific fluorescence spectrum detection and characterization of hASIC1a channels upon toxin mambalgin-1 binding in live mammalian cells. Chem Commun (Camb). 2015 May 11;51(38):8153-6. doi: 10.1039/c5cc01418b. Epub 2015 Apr 15.
Ref 24 Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain. Pain. 2016 Mar;157(3):552-559. doi: 10.1097/j.pain.0000000000000397.
Ref 25 One-pot hydrazide-based native chemical ligation for efficient chemical synthesis and structure determination of toxin Mambalgin-1. Chem Commun (Camb). 2014 Jun 4;50(44):5837-9. doi: 10.1039/c4cc00779d.
Ref 26 Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition. J Biol Chem. 2016 Feb 5;291(6):2616-29. doi: 10.1074/jbc.M115.702373. Epub 2015 Dec 17.
Ref 27 Cryo-EM structure of the ASIC1a-mambalgin-1 complex reveals that the peptide toxin mambalgin-1 inhibits acid-sensing ion channels through an unusual allosteric effect. Cell Discov. 2018 Jun 5;4:27. doi: 10.1038/s41421-018-0026-1. eCollection 2018.
Ref 28 Binding site and inhibitory mechanism of the mambalgin-2 pain-relieving peptide on acid-sensing ion channel 1a. J Biol Chem. 2014 May 9;289(19):13363-73. doi: 10.1074/jbc.M114.561076. Epub 2014 Apr 2.
Ref 29 Total synthesis of mambalgin-1/2/3 by two-segment hydrazide-based native chemical ligation. J Pept Sci. 2016 May;22(5):320-6. doi: 10.1002/psc.2868. Epub 2016 Mar 15.
Ref 30 Chemical synthesis, 3D structure, and ASIC binding site of the toxin mambalgin-2. Angew Chem Int Ed Engl. 2014 Jan 20;53(4):1017-20. doi: 10.1002/anie.201308898. Epub 2013 Dec 9.
Ref 31 A novel sea anemone peptide that inhibits acid-sensing ion channels. Peptides. 2014 Mar;53:3-12. doi: 10.1016/j.peptides.2013.06.003. Epub 2013 Jun 10.
Ref 32 New APETx-like peptides from sea anemone Heteractis crispa modulate ASIC1a channels. Peptides. 2018 Jun;104:41-49. doi: 10.1016/j.peptides.2018.04.013. Epub 2018 Apr 22.
Ref 33 APETx-Like Peptides from the Sea Anemone Heteractis crispa, Diverse in Their Effect on ASIC1a and ASIC3 Ion Channels. Toxins (Basel). 2020 Apr 20;12(4):266. doi: 10.3390/toxins12040266.
Ref 34 Nicotinic Acetylcholine Receptors Are Novel Targets of APETx-like Toxins from the Sea Anemone Heteractis magnifica. Toxins (Basel). 2022 Oct 11;14(10):697. doi: 10.3390/toxins14100697.
Ref 35 A Tale of Toxin Promiscuity: The Versatile Pharmacological Effects of Hcr 1b-2 Sea Anemone Peptide on Voltage-Gated Ion Channels. Mar Drugs. 2022 Feb 17;20(2):147. doi: 10.3390/md20020147.
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