ASIC3_RAT
ID ASIC3_RAT Reviewed; 533 AA.
AC O35240;
DT 13-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Acid-sensing ion channel 3;
DE Short=ASIC3;
DE AltName: Full=Amiloride-sensitive cation channel 3;
DE AltName: Full=Dorsal root ASIC;
DE Short=DRASIC;
GN Name=Asic3; Synonyms=Accn3, Drasic;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=9261094; DOI=10.1074/jbc.272.34.20975;
RA Waldmann R., Bassilana F., de Weille J.R., Champigny G., Heurteaux C.,
RA Lazdunski M.;
RT "Molecular cloning of a non-inactivating proton-gated Na+ channel specific
RT for sensory neurons.";
RL J. Biol. Chem. 272:20975-20978(1997).
RN [2]
RP INTERACTION WITH ASIC1.
RC STRAIN=Wistar; TISSUE=Brain;
RX PubMed=9368048; DOI=10.1074/jbc.272.47.29778;
RA Lingueglia E., de Weille J.R., Bassilana F., Heurteaux C., Sakai H.,
RA Waldmann R., Lazdunski M.;
RT "A modulatory subunit of acid sensing ion channels in brain and dorsal root
RT ganglion cells.";
RL J. Biol. Chem. 272:29778-29783(1997).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=9707631; DOI=10.1073/pnas.95.17.10240;
RA Chen C.-C., England S., Akopian A.N., Wood J.N.;
RT "A sensory neuron-specific, proton-gated ion channel.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:10240-10245(1998).
RN [4]
RP MUTAGENESIS OF VAL-20; PHE-21 AND THR-26.
RX PubMed=10187795; DOI=10.1074/jbc.274.15.10129;
RA Coscoy S., de Weille J.R., Lingueglia E., Lazdunski M.;
RT "The pre-transmembrane 1 domain of acid-sensing ion channels participates
RT in the ion pore.";
RL J. Biol. Chem. 274:10129-10132(1999).
RN [5]
RP TISSUE SPECIFICITY.
RX PubMed=10842183; DOI=10.1074/jbc.m004114200;
RA Babinski K., Catarsi S., Biagini G., Seguela P.;
RT "Mammalian ASIC2a and ASIC3 subunits co-assemble into heteromeric proton-
RT gated channels sensitive to Gd3+.";
RL J. Biol. Chem. 275:28519-28525(2000).
RN [6]
RP INDUCTION, AND INHIBITION BY DRUGS.
RX PubMed=11588175; DOI=10.1523/jneurosci.21-20-08026.2001;
RA Voilley N., de Weille J.R., Mamet J., Lazdunski M.;
RT "Nonsteroid anti-inflammatory drugs inhibit both the activity and the
RT inflammation-induced expression of acid-sensing ion channels in
RT nociceptors.";
RL J. Neurosci. 21:8026-8033(2001).
RN [7]
RP REGULATION BY LACTATE, AND FUNCTION.
RX PubMed=11528414; DOI=10.1038/nn0901-869;
RA Immke D.C., McCleskey E.W.;
RT "Lactate enhances the acid-sensing Na+ channel on ischemia-sensing
RT neurons.";
RL Nat. Neurosci. 4:869-870(2001).
RN [8]
RP REGULATION BY NPFF.
RX PubMed=11587714; DOI=10.1016/s0028-3908(01)00107-1;
RA Catarsi S., Babinski K., Seguela P.;
RT "Selective modulation of heteromeric ASIC proton-gated channels by
RT neuropeptide FF.";
RL Neuropharmacology 41:592-600(2001).
RN [9]
RP FUNCTION.
RX PubMed=11120882; DOI=10.1073/pnas.98.2.711;
RA Sutherland S.P., Benson C.J., Adelman J.P., McCleskey E.W.;
RT "Acid-sensing ion channel 3 matches the acid-gated current in cardiac
RT ischemia-sensing neurons.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:711-716(2001).
RN [10]
RP INDUCTION.
RX PubMed=12486159; DOI=10.1523/jneurosci.22-24-10662.2002;
RA Mamet J., Baron A., Lazdunski M., Voilley N.;
RT "Proinflammatory mediators, stimulators of sensory neuron excitability via
RT the expression of acid-sensing ion channels.";
RL J. Neurosci. 22:10662-10670(2002).
RN [11]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=11842212; DOI=10.1073/pnas.042688199;
RA Alvarez de la Rosa D., Zhang P., Shao D., White F., Canessa C.M.;
RT "Functional implications of the localization and activity of acid-sensitive
RT channels in rat peripheral nervous system.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:2326-2331(2002).
RN [12]
RP DEVELOPMENTAL STAGE, AND INDUCTION BY NGFB.
RX PubMed=14522957; DOI=10.1074/jbc.m309468200;
RA Mamet J., Lazdunski M., Voilley N.;
RT "How nerve growth factor drives physiological and inflammatory expressions
RT of acid-sensing ion channel 3 in sensory neurons.";
RL J. Biol. Chem. 278:48907-48913(2003).
RN [13]
RP REGULATION BY LACTATE AND CALCIUM.
RX PubMed=12526774; DOI=10.1016/s0896-6273(02)01130-3;
RA Immke D.C., McCleskey E.W.;
RT "Protons open acid-sensing ion channels by catalyzing relief of Ca2+
RT blockade.";
RL Neuron 37:75-84(2003).
RN [14]
RP FUNCTION.
RX PubMed=12668052; DOI=10.1016/s0028-3908(03)00047-9;
RA Deval E., Baron A., Lingueglia E., Mazarguil H., Zajac J.-M., Lazdunski M.;
RT "Effects of neuropeptide SF and related peptides on acid sensing ion
RT channel 3 and sensory neuron excitability.";
RL Neuropharmacology 44:662-671(2003).
RN [15]
RP INHIBITION BY APETX2 TOXIN.
RX PubMed=15044953; DOI=10.1038/sj.emboj.7600177;
RA Diochot S., Baron A., Rash L.D., Deval E., Escoubas P., Scarzello S.,
RA Salinas M., Lazdunski M.;
RT "A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive
RT channel in sensory neurons.";
RL EMBO J. 23:1516-1525(2004).
RN [16]
RP MUTAGENESIS OF THR-40 AND SER-523, AND PHOSPHORYLATION AT THR-40 AND
RP SER-523.
RX PubMed=14976185; DOI=10.1074/jbc.m313078200;
RA Deval E., Salinas M., Baron A., Lingueglia E., Lazdunski M.;
RT "ASIC2b-dependent regulation of ASIC3, an essential acid-sensing ion
RT channel subunit in sensory neurons via the partner protein PICK-1.";
RL J. Biol. Chem. 279:19531-19539(2004).
RN [17]
RP INTERACTION WITH DLG4, AND SUBCELLULAR LOCATION.
RX PubMed=15317815; DOI=10.1074/jbc.m405874200;
RA Hruska-Hageman A.M., Benson C.J., Leonard A.S., Price M.P., Welsh M.J.;
RT "PSD-95 and Lin-7b interact with acid-sensing ion channel-3 and have
RT opposite effects on H+- gated current.";
RL J. Biol. Chem. 279:46962-46968(2004).
RN [18]
RP FUNCTION, INTERACTION WITH STOM, AND SUBCELLULAR LOCATION.
RX PubMed=22850675; DOI=10.1038/emboj.2012.203;
RA Brand J., Smith E.S., Schwefel D., Lapatsina L., Poole K., Omerbasic D.,
RA Kozlenkov A., Behlke J., Lewin G.R., Daumke O.;
RT "A stomatin dimer modulates the activity of acid-sensing ion channels.";
RL EMBO J. 31:3635-3646(2012).
RN [19]
RP SUBUNIT, AND INTERACTION WITH CONO-RFAMIDE CNF-TX1.1.
RX PubMed=28396446; DOI=10.1073/pnas.1616232114;
RA Reimers C., Lee C.H., Kalbacher H., Tian Y., Hung C.H., Schmidt A.,
RA Prokop L., Kauferstein S., Mebs D., Chen C.C., Gruender S.;
RT "Identification of a cono-RFamide from the venom of Conus textile that
RT targets ASIC3 and enhances muscle pain.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:E3507-E3515(2017).
CC -!- FUNCTION: Cation channel with high affinity for sodium, which is gated
CC by extracellular protons and inhibited by the diuretic amiloride.
CC Generates a biphasic current with a fast inactivating and a slow
CC sustained phase. In sensory neurons is proposed to mediate the pain
CC induced by acidosis that occurs in ischemic, damaged or inflamed
CC tissue. May be involved in hyperalgesia. May play a role in
CC mechanoreception. Heteromeric channel assembly seems to modulate
CC channel properties. {ECO:0000269|PubMed:11120882,
CC ECO:0000269|PubMed:11528414, ECO:0000269|PubMed:12668052,
CC ECO:0000269|PubMed:22850675, ECO:0000269|PubMed:28396446}.
CC -!- SUBUNIT: Homotrimer or heterotrimer with other ASIC proteins (By
CC similarity). Interacts with LIN7B, MAGI1 and GOPC (By similarity).
CC Interacts with DLG4 and ASIC2. Interacts with STOM; this regulates
CC channel activity. Homotrimeric ASIC3 and ASIC3-containing heterotrimers
CC interact with the cono-RFamide CNF-Tx1.1, and probably CNF-Tx1.2 and
CC CNF-Tx1.3 (AC P0DL71) (PubMed:28396446). {ECO:0000250,
CC ECO:0000269|PubMed:15317815, ECO:0000269|PubMed:22850675,
CC ECO:0000269|PubMed:28396446, ECO:0000269|PubMed:9368048}.
CC -!- INTERACTION:
CC O35240; Q9JJ19: Slc9a3r1; NbExp=5; IntAct=EBI-982374, EBI-982391;
CC O35240; Q920G2: Slc9a3r2; NbExp=2; IntAct=EBI-982374, EBI-982439;
CC O35240; D4A100: Stoml3; NbExp=2; IntAct=EBI-982374, EBI-15615743;
CC O35240; Q63ZW7-3: Patj; Xeno; NbExp=2; IntAct=EBI-982374, EBI-8158524;
CC O35240; P54116: Stom; Xeno; NbExp=3; IntAct=EBI-982374, EBI-8004826;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane
CC {ECO:0000250}; Multi-pass membrane protein {ECO:0000250}. Note=In part
CC cytoplasmic in cochlea cells (By similarity). Cell surface expression
CC may be stabilized by interaction with LIN7B and cytoplasmic retention
CC by interaction with DLG4. {ECO:0000250, ECO:0000269|PubMed:11842212,
CC ECO:0000269|PubMed:15317815, ECO:0000269|PubMed:22850675}.
CC -!- TISSUE SPECIFICITY: Expressed in sciatic nerve and dorsal root ganglion
CC (at protein level). Expressed in sensory neurons of dorsal root
CC ganglion. Expressed in Golgi interneurons in the granular layer. Also
CC found in superior cervical ganglia, spinal cord and brain stem.
CC {ECO:0000269|PubMed:10842183, ECO:0000269|PubMed:11842212,
CC ECO:0000269|PubMed:9261094, ECO:0000269|PubMed:9707631}.
CC -!- DEVELOPMENTAL STAGE: Expression is first detected at E15.5. Strongly
CC expressed perinatally. {ECO:0000269|PubMed:14522957}.
CC -!- INDUCTION: Transcriptionally regulated by the proinflammatory mediators
CC nerve growth factor, serotonin, interleukin-1 and bradykinin. Up-
CC regulation upon tissue inflammation is abolished by anti-inflammatory
CC drugs. {ECO:0000269|PubMed:11588175, ECO:0000269|PubMed:12486159,
CC ECO:0000269|PubMed:14522957}.
CC -!- DOMAIN: The PDZ domain-binding motif is involved in interaction with
CC LIN7A, GOPC and MAGI1/BAIAP1. {ECO:0000250}.
CC -!- PTM: Phosphorylated by PKA (By similarity). Phosphorylated by PKC. In
CC vitro, PRKCABP/PICK-1 is necessary for PKC phosphorylation and
CC activation of a ASIC3/ACCN3-ASIC2/ASIC2b channel, but does not activate
CC a homomeric ASIC3/ACCN3 channel. {ECO:0000250,
CC ECO:0000269|PubMed:14976185}.
CC -!- MISCELLANEOUS: Potentiated by FMRFamide-related neuropeptides (By
CC similarity). Sensitized and potentiated by NPFF and NPSF. Regulated by
CC lactate and Ca(2+). Specifically inhibited by APETx2, a sea anemone
CC toxin. Inhibited by anti-inflammatory drugs like salicylic acid.
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the amiloride-sensitive sodium channel (TC
CC 1.A.6) family. ASIC3 subfamily. {ECO:0000305}.
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DR EMBL; AF013598; AAB69328.1; -; mRNA.
DR RefSeq; NP_775158.1; NM_173135.1.
DR AlphaFoldDB; O35240; -.
DR SMR; O35240; -.
DR DIP; DIP-35759N; -.
DR IntAct; O35240; 5.
DR MINT; O35240; -.
DR STRING; 10116.ENSRNOP00000011300; -.
DR BindingDB; O35240; -.
DR ChEMBL; CHEMBL5757; -.
DR TCDB; 1.A.6.1.2; the epithelial na(+) channel (enac) family.
DR GlyGen; O35240; 2 sites.
DR iPTMnet; O35240; -.
DR PhosphoSitePlus; O35240; -.
DR PaxDb; O35240; -.
DR Ensembl; ENSRNOT00000011300; ENSRNOP00000011300; ENSRNOG00000008380.
DR GeneID; 286920; -.
DR KEGG; rno:286920; -.
DR CTD; 9311; -.
DR RGD; 708578; Asic3.
DR eggNOG; KOG4294; Eukaryota.
DR GeneTree; ENSGT00940000162081; -.
DR HOGENOM; CLU_020415_1_2_1; -.
DR InParanoid; O35240; -.
DR OMA; SDICVFA; -.
DR OrthoDB; 686369at2759; -.
DR PhylomeDB; O35240; -.
DR TreeFam; TF330663; -.
DR Reactome; R-RNO-2672351; Stimuli-sensing channels.
DR PRO; PR:O35240; -.
DR Proteomes; UP000002494; Chromosome 4.
DR Bgee; ENSRNOG00000008380; Expressed in cerebellum and 2 other tissues.
DR Genevisible; O35240; RN.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0044736; F:acid-sensing ion channel activity; IBA:GO_Central.
DR GO; GO:0005261; F:cation channel activity; ISO:RGD.
DR GO; GO:0042931; F:enterobactin transmembrane transporter activity; ISO:RGD.
DR GO; GO:0015280; F:ligand-gated sodium channel activity; IDA:MGI.
DR GO; GO:0006812; P:cation transport; ISO:RGD.
DR GO; GO:0050907; P:detection of chemical stimulus involved in sensory perception; ISO:RGD.
DR GO; GO:0050968; P:detection of chemical stimulus involved in sensory perception of pain; ISO:RGD.
DR GO; GO:0050974; P:detection of mechanical stimulus involved in sensory perception; ISO:RGD.
DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; ISO:RGD.
DR GO; GO:0050961; P:detection of temperature stimulus involved in sensory perception; ISO:RGD.
DR GO; GO:0050965; P:detection of temperature stimulus involved in sensory perception of pain; ISO:RGD.
DR GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl.
DR GO; GO:0034220; P:ion transmembrane transport; IDA:RGD.
DR GO; GO:0010447; P:response to acidic pH; IDA:MGI.
DR GO; GO:0009408; P:response to heat; ISO:RGD.
DR GO; GO:0009612; P:response to mechanical stimulus; ISO:RGD.
DR GO; GO:0050915; P:sensory perception of sour taste; ISO:RGD.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IBA:GO_Central.
DR GO; GO:0006814; P:sodium ion transport; IDA:MGI.
DR InterPro; IPR001873; ENaC.
DR InterPro; IPR004724; ENaC_chordates.
DR InterPro; IPR020903; ENaC_CS.
DR PANTHER; PTHR11690; PTHR11690; 1.
DR Pfam; PF00858; ASC; 1.
DR PRINTS; PR01078; AMINACHANNEL.
DR TIGRFAMs; TIGR00859; ENaC; 1.
DR PROSITE; PS01206; ASC; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cytoplasm; Disulfide bond; Glycoprotein; Ion channel;
KW Ion transport; Membrane; Phosphoprotein; Reference proteome; Sodium;
KW Sodium channel; Sodium transport; Transmembrane; Transmembrane helix;
KW Transport.
FT CHAIN 1..533
FT /note="Acid-sensing ion channel 3"
FT /id="PRO_0000181303"
FT TOPO_DOM 1..19
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 20..40
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 41..435
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 436..456
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 457..533
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 286..310
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 530..533
FT /note="PDZ-binding"
FT /evidence="ECO:0000250"
FT SITE 26
FT /note="Potassium ion selectivity and permeability"
FT MOD_RES 40
FT /note="Phosphothreonine; by PKC"
FT /evidence="ECO:0000305|PubMed:14976185"
FT MOD_RES 523
FT /note="Phosphoserine; by PKC"
FT /evidence="ECO:0000305|PubMed:14976185"
FT CARBOHYD 176
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 400
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 93..187
FT /evidence="ECO:0000250"
FT DISULFID 165..172
FT /evidence="ECO:0000250"
FT DISULFID 283..372
FT /evidence="ECO:0000250"
FT DISULFID 317..368
FT /evidence="ECO:0000250"
FT DISULFID 321..366
FT /evidence="ECO:0000250"
FT DISULFID 330..352
FT /evidence="ECO:0000250"
FT DISULFID 332..344
FT /evidence="ECO:0000250"
FT MUTAGEN 20
FT /note="V->P: No effect on selectivity or channel function."
FT /evidence="ECO:0000269|PubMed:10187795"
FT MUTAGEN 21
FT /note="F->S: Loss of channel function."
FT /evidence="ECO:0000269|PubMed:10187795"
FT MUTAGEN 26
FT /note="T->K: Alters selectivity of the channel for sodium.
FT No effect on channel function."
FT /evidence="ECO:0000269|PubMed:10187795"
FT MUTAGEN 40
FT /note="T->G: Loss of regulation by PKC through PRKCABP;
FT when associated with G-523."
FT /evidence="ECO:0000269|PubMed:14976185"
FT MUTAGEN 523
FT /note="S->G: Loss of regulation by PKC through PRKCABP;
FT when associated with G-40."
FT /evidence="ECO:0000269|PubMed:14976185"
SQ SEQUENCE 533 AA; 59227 MW; 294B57322C74B3DC CRC64;
MKPRSGLEEA QRRQASDIRV FASSCTMHGL GHIFGPGGLT LRRGLWATAV LLSLAAFLYQ
VAERVRYYGE FHHKTTLDER ESHQLTFPAV TLCNINPLRR SRLTPNDLHW AGTALLGLDP
AEHAAYLRAL GQPPAPPGFM PSPTFDMAQL YARAGHSLED MLLDCRYRGQ PCGPENFTVI
FTRMGQCYTF NSGAHGAELL TTPKGGAGNG LEIMLDVQQE EYLPIWKDME ETPFEVGIRV
QIHSQDEPPA IDQLGFGAAP GHQTFVSCQQ QQLSFLPPPW GDCNTASLDP DDFDPEPSDP
LGSPRPRPSP PYSLIGCRLA CESRYVARKC GCRMMHMPGN SPVCSPQQYK DCASPALDAM
LRKDTCVCPN PCATTRYAKE LSMVRIPSRA SARYLARKYN RSESYITENV LVLDIFFEAL
NYEAVEQKAA YEVSELLGDI GGQMGLFIGA SLLTILEILD YLCEVFQDRV LGYFWNRRSA
QKRSGNTLLQ EELNGHRTHV PHLSLGPRPP TTPCAVTKTL SASHRTCYLV TRL
