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Protein

Acid-sensing ion channel 1

Gene

Asic1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 Ca2+ while isoform 1 cannot. Heteromeric channels composed of isoform 2 and isoform 3 are active but have a lower pH-sensitivity. Mediates glutamate-independent Ca2+ entry into neurons upon acidosis. This Ca2+ overloading is toxic for cortical neurons and may be in part responsible for ischemic brain injury. Heteromeric channel assembly seems to modulate channel properties.7 Publications

Miscellaneous

Potentiated by Ca2+, Mg2+, Ba2+, multivalent cations and potentiated by FMRFamide-related neuropeptides. pH dependence may be regulated by serine proteases. Inhibited by anti-inflammatory drugs like salicylic acid. Isoform 1 homomultimeric channel is specifically and reversibly inhibited by psalmotoxin-1, a spider venom toxin, while isoform 2 and other ASICs are insensitive.

Enzyme regulationi

Inhibited by the diuretic amiloride.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei71Important for channel gatingBy similarity1
Sitei79Important for channel desensitizingBy similarity1
Sitei175Important residue in interaction with the spider venom Pi-theraphotoxin-Hm3a, which can explain functional difference between ASIC1a and ASIC1b1 Publication1
Sitei177Important residue for interaction with the spider venom Pi-theraphotoxin-Hm3a, which can explain functional difference between ASIC1a and ASIC1b1 Publication1
Sitei287Important for channel gatingBy similarity1
Sitei349Important for interaction with the snake venom mambalgin-21 Publication1
Sitei350Important for interaction with the snake venom mambalgin-1 and mambalgin-2 toxins, probably binds to its residue L-53; Important for interaction with the spider venom Pi-hexatoxin-Hi1a and psalmotoxin-15 Publications1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionIon channel, Sodium channel
Biological processCalcium transport, Ion transport, Sodium transport, Transport
LigandCalcium, Sodium

Enzyme and pathway databases

ReactomeiR-RNO-2672351. Stimuli-sensing channels.

Protein family/group databases

TCDBi1.A.6.1.2. the epithelial na(+) channel (enac) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Acid-sensing ion channel 11 Publication
Short name:
ASIC11 Publication
Alternative name(s):
Amiloride-sensitive cation channel 2, neuronal
Brain sodium channel 2
Short name:
BNaC2
Gene namesi
Name:Asic1
Synonyms:Accn2, Bnac2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 7

Organism-specific databases

RGDi71062. Asic1.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 45CytoplasmicBy similarityAdd BLAST45
Transmembranei46 – 69HelicalBy similarityAdd BLAST24
Topological domaini70 – 425ExtracellularBy similarityAdd BLAST356
Transmembranei426 – 452Discontinuously helicalBy similarityAdd BLAST27
Topological domaini453 – 526CytoplasmicBy similarityAdd BLAST74

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi83S → P: No effect. Increases desensitization rates; when associated with L-84 and M-85. 1 Publication1
Mutagenesisi84Q → L: No effect. Increases desensitization rates; when associated with P-83 and M-85. 1 Publication1
Mutagenesisi85L → M: No effect. Increases desensitization rates; when associated with P-83 and L-84. 1 Publication1
Mutagenesisi100F → L: No effect on channel activation and inactivation. 1 Publication1
Mutagenesisi103V → L: No effect on channel activation and inactivation. 1 Publication1
Mutagenesisi105K → Y: Activated and inactivated at lower pH. 1 Publication1
Mutagenesisi106N → P: Activated and inactivated at lower pH. 1 Publication1
Mutagenesisi128 – 131QMAD → HLVE: No effect on desensitization rates. 1 Publication4
Mutagenesisi173H → S: No significant decrease in inhibition by the spider pi-theraphotoxin-Hm3a. 1 Publication1
Mutagenesisi174F → Y: No significant decrease in inhibition by the spider pi-theraphotoxin-Hm3a. 1 Publication1
Mutagenesisi175R → C: 18-fold decrease in inhibition by the spider pi-theraphotoxin-Hm3a. 1 Publication1
Mutagenesisi177E → G: 10-fold decrease in inhibition by the spider pi-theraphotoxin-Hm3a. 1 Publication1
Mutagenesisi178A → P: No significant decrease in inhibition by the spider pi-theraphotoxin-Hm3a. 1 Publication1
Mutagenesisi178A → V: No significant decrease in inhibition by the spider pi-theraphotoxin-Hm3a. 1 Publication1
Mutagenesisi190R → K: Small decrease in inhibition by the snake mambalgin-2 toxin; RDQ-KQE mutant. 1 Publication1
Mutagenesisi235E → A: No change in the shift of pH for both activation and desensitization by the spider venom psalmotoxin-1. 1 Publication1
Mutagenesisi259 – 260DQ → QE: Small decrease in inhibition by the snake mambalgin-2 toxin; RDQ-KQE mutant. 1 Publication2
Mutagenesisi316Y → A: No change in the shift of pH for both activation and desensitization by the spider venom psalmotoxin-1. 1 Publication1
Mutagenesisi349 – 350DF → GL: Complete loss in inhibition by 200 nM of the snake mambalgin-2 toxin. 1 Publication2
Mutagenesisi349D → G: High decrease in inhibition by the snake mambalgin-2 toxin. 1 Publication1
Mutagenesisi350F → A: Complete loss of inhibition by the spider Pi-hexatoxin-Hi1a, and by the snake mambalgin-2 toxin. Potentiated by the spider pi-theraphotoxin-Hm3a (at both pH 7.35 and 7.45) and inhibited at higher toxin concentration at pH 7.35. Complete loss in the shift of pH for both activation and desensitization by the spider venom psalmotoxin-1. 4 Publications1
Mutagenesisi350F → L: 37-fold decrease in inbibition by the snake mambalgin-1 toxin. Very high decrease in inhibition by the snake mambalgin-2 toxin. 2 Publications1
Mutagenesisi352V → A: Moderate decrease in inhibition by the snake mambalgin-2 toxin. 1 Publication1
Mutagenesisi354K → A: No change in the shift of pH for both activation and desensitization by the spider venom psalmotoxin-1. 1 Publication1
Mutagenesisi356Q → S: Moderate decrease in inhibition by the snake mambalgin-2 toxin. 1 Publication1
Mutagenesisi357E → N: Moderate decrease in inhibition by the snake mambalgin-2 toxin. 1 Publication1
Mutagenesisi425E → G: Reduction of Ca(2+) block. Loss of Ca(2+) block; when associated with C-432. 1 Publication1
Mutagenesisi431G → V or F: Constitutive channel activity. 1 Publication1
Mutagenesisi432D → A: Reduction of Ca(2+) block. 1 Publication1
Mutagenesisi432D → C: Reduction of Ca(2+) block. Loss of Ca(2+) block; when associated with G-425. 1 Publication1
Mutagenesisi436Q → N: No effect on Ca(2+) block. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL3562170.
GuidetoPHARMACOLOGYi684.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001813001 – 526Acid-sensing ion channel 1Add BLAST526

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi93 ↔ 194By similarity
Disulfide bondi172 ↔ 179By similarity
Disulfide bondi290 ↔ 365By similarity
Disulfide bondi308 ↔ 361By similarity
Disulfide bondi312 ↔ 359By similarity
Disulfide bondi321 ↔ 343By similarity
Disulfide bondi323 ↔ 335By similarity
Glycosylationi366N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi393N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei477PhosphoserineBy similarity1
Modified residuei497PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylation by PKA regulates interaction with PRKCABP and subcellular location. Phosphorylation by PKC may regulate the channel (By similarity).By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PRIDEiP55926.

PTM databases

iPTMnetiP55926.
PhosphoSitePlusiP55926.
SwissPalmiP55926.

Expressioni

Tissue specificityi

Expressed in dorsal root ganglia and sciatic nerve (at protein level). Widely distributed throughout the brain. Expressed in olfactory bulb, neo and allocortical regions, dentate granule cells, pyramidal cells of CA1-CA3 subfields of the hippocampal formation, habenula, basolateral amygdaloid nuclei, and in the Purkinje and granule cells of the cerebellum. Diffusely detected over most other regions of the basal ganglia, including thalamic nuclei, substantia nigra, striatum and globus pallidus, hypothalamus, midbrain, pons, medulla and choroid plexus. Isoform 3 is expressed only in dorsal root ganglion (DRG) while isoform 1 is expressed in DRG, spinal chord, trigeminal ganglia and the trigeminal mesencephalic nucleus.4 Publications

Inductioni

Up-regulation upon tissues inflammation is abolished by anti-inflammatory drugs.1 Publication

Gene expression databases

BgeeiENSRNOG00000059765.
ExpressionAtlasiP55926. differential.
GenevisibleiP55926. RN.

Interactioni

Subunit structurei

Homotrimer or heterotrimer with other ASIC proteins (By similarity). Interacts with STOM and PRKCABP (By similarity). Interacts with ASIC2. Interacts with the spider venom Pi-hexatoxin-Hi1a (PubMed:28320941). Homotrimer of Asic1a interacts with the spider venom psalmotoxin-1 (PubMed:10829030, PubMed:26248594). Homotrimer of Asic1a and Asic1b and heterotrimer of Asic1a/Asic1b interact with the spider venom Pi-theraphotoxin-Hm3a (PubMed:28327374). Homotrimer of Asic1a interacts with the snake venom mambalgin-1, mambalgin-2 and mambalgin-3 (PubMed:23034652, PubMed:23624383, PubMed:24323786, PubMed:24695733, PubMed:26680001). Homotrimer of Asic1b interacts with the snake venom mambalgin-1, mambalgin-2 and mambalgin-3 (PubMed:23034652, PubMed:23624383, PubMed:24323786, PubMed:26680001). Heterotrimer of Asic1a-Asic1b interacts with the snake venom mambalgin-1 and mambalgin-2 (PubMed:23034652). Heterotrimer of Asic1a-Asic2a interacts with the snake venom mambalgin-1, mambalgin-2 and mambalgin-3 (PubMed:23034652, PubMed:23624383, PubMed:26680001). Heterotrimer of Asic1a-Asic2b interacts with the snake venom mambalgin-1 and mambalgin-2 (PubMed:23034652).By similarity10 Publications

Protein-protein interaction databases

MINTiMINT-223538.

Structurei

3D structure databases

ProteinModelPortaliP55926.
SMRiP55926.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni20 – 25Involved in divalent cations permeability6

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi442 – 444Selectivity filterCurated3

Domaini

Channel opening involves a conformation change that affects primarily the extracellular domain and the second transmembrane helix and its orientation in the membrane. In the open state, the second transmembrane helix is nearly perpendicular to the plane of the membrane; in the desensitized state it is strongly tilted. Besides, the second transmembrane domain is discontinuously helical in the open state. The GAS motif of the selectivity filter is in an extended conformation, giving rise to a distinct kink in the polypeptide chain. A domain swap between subunits gives rise to a full-length transmembrane helix (By similarity).By similarity

Sequence similaritiesi

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

GeneTreeiENSGT00760000119120.
HOGENOMiHOG000247010.
HOVERGENiHBG004150.
InParanoidiP55926.
KOiK04829.
OMAiANFQMIN.
OrthoDBiEOG091G053J.
PhylomeDBiP55926.
TreeFamiTF330663.

Family and domain databases

InterProiView protein in InterPro
IPR001873. ENaC.
IPR004724. ENaC_chordates.
IPR020903. ENaC_CS.
PANTHERiPTHR11690. PTHR11690. 1 hit.
PfamiView protein in Pfam
PF00858. ASC. 1 hit.
PRINTSiPR01078. AMINACHANNEL.
TIGRFAMsiTIGR00859. ENaC. 1 hit.
PROSITEiView protein in PROSITE
PS01206. ASC. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P55926-1) [UniParc]FASTAAdd to basket
Also known as: ASIC-alpha, asic1alpha

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MELKTEEEEV GGVQPVSIQA FASSSTLHGL AHIFSYERLS LKRALWALCF
60 70 80 90 100
LGSLAVLLCV CTERVQYYFC YHHVTKLDEV AASQLTFPAV TLCNLNEFRF
110 120 130 140 150
SQVSKNDLYH AGELLALLNN RYEIPDTQMA DEKQLEILQD KANFRSFKPK
160 170 180 190 200
PFNMREFYDR AGHDIRDMLL SCHFRGEACS AEDFKVVFTR YGKCYTFNSG
210 220 230 240 250
QDGRPRLKTM KGGTGNGLEI MLDIQQDEYL PVWGETDETS FEAGIKVQIH
260 270 280 290 300
SQDEPPFIDQ LGFGVAPGFQ TFVSCQEQRL IYLPSPWGTC NAVTMDSDFF
310 320 330 340 350
DSYSITACRI DCETRYLVEN CNCRMVHMPG DAPYCTPEQY KECADPALDF
360 370 380 390 400
LVEKDQEYCV CEMPCNLTRY GKELSMVKIP SKASAKYLAK KFNKSEQYIG
410 420 430 440 450
ENILVLDIFF EVLNYETIEQ KKAYEIAGLL GDIGGQMGLF IGASILTVLE
460 470 480 490 500
LFDYAYEVIK HRLCRRGKCQ KEAKRSSADK GVALSLDDVK RHNPCESLRG
510 520
HPAGMTYAAN ILPHHPARGT FEDFTC
Length:526
Mass (Da):59,641
Last modified:November 1, 1997 - v1
Checksum:i5462A7786E2A1726
GO
Isoform 2 (identifier: P55926-2) [UniParc]FASTAAdd to basket
Also known as: ASIC-beta2

The sequence of this isoform differs from the canonical sequence as follows:
     1-185: Missing.
     186-186: V → MADIWGPHHH...VIALGAFLCQ

Note: Inactive.
Show »
Length:425
Mass (Da):47,563
Checksum:i8B4A9EDFCE348B89
GO
Isoform 3 (identifier: P55926-3) [UniParc]FASTAAdd to basket
Also known as: ASIC-beta, ASIC1b

The sequence of this isoform differs from the canonical sequence as follows:
     1-185: Missing.
     186-186: V → MPIQIFCSVS...GPCGPHNFSV

Note: Blocked by Ca2+. Mutagenesis of Asp-465 to Asn reduces Ca2+ block.Curated
Show »
Length:559
Mass (Da):62,217
Checksum:i0F438117B95C18E5
GO

Sequence cautioni

The sequence CAA07080 differs from that shown. Reason: Frameshift at positions 119, 122 and 142.Curated
Isoform 3 : The sequence CAA07080 differs from that shown. Reason: Frameshift at positions 7 and 14.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Isoform 3 (identifier: P55926-3)
Sequence conflicti128T → S in CAA07080 (PubMed:9707631).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0155971 – 185Missing in isoform 2 and isoform 3. 3 PublicationsAdd BLAST185
Alternative sequenceiVSP_015598186V → MADIWGPHHHRQQQDSSESE EEEEKEMEAGSELDEGDDSP RDLVAFANSCTLHGASHVFV EGGPGPRQALWAVAFVIALG AFLCQ in isoform 2. 1 Publication1
Alternative sequenceiVSP_015599186V → MPIQIFCSVSFSSGEEAPGS MADIWGPHHHRQQQDSSESE EEEEKEMEAGSELDEGDDSP RDLVAFANSCTLHGASHVFV EGGPGPRQALWAVAFVIALG AFLCQVGDRVAYYLSYPHVT LLDEVATTELVFPAVTFCNT NAVRLSQLSYPDLLYLAPML GLDESDDPGVPLAPPGPEAF SGEPFNLHRFYNRSCHRLED MLLYCSYCGGPCGPHNFSV in isoform 3. 2 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U94403 mRNA. Translation: AAB53002.1.
AJ006519 mRNA. Translation: CAA07080.1. Frameshift.
AJ309926 mRNA. Translation: CAC44267.1.
AB049451 mRNA. Translation: BAB39864.1.
RefSeqiNP_077068.1. NM_024154.2. [P55926-1]
XP_006257440.1. XM_006257378.3. [P55926-3]
UniGeneiRn.37385.

Genome annotation databases

EnsembliENSRNOT00000077175; ENSRNOP00000072206; ENSRNOG00000059765. [P55926-2]
ENSRNOT00000088191; ENSRNOP00000068902; ENSRNOG00000059765. [P55926-1]
GeneIDi79123.
KEGGirno:79123.

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiASIC1_RAT
AccessioniPrimary (citable) accession number: P55926
Secondary accession number(s): O88762, Q91YB8, Q99NA1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: November 22, 2017
This is version 143 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families