APAM_APIME
ID APAM_APIME Reviewed; 46 AA.
AC P01500;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 2.
DT 25-MAY-2022, entry version 103.
DE RecName: Full=Apamin {ECO:0000303|PubMed:1795707, ECO:0000303|PubMed:2013287, ECO:0000303|PubMed:3242598};
DE Short=APM {ECO:0000303|PubMed:32289477};
DE AltName: Full=Apamine {ECO:0000303|PubMed:5601655};
DE Flags: Precursor;
OS Apis mellifera (Honeybee).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Hymenoptera; Apocrita; Aculeata; Apoidea; Apidae;
OC Apis.
OX NCBI_TaxID=7460;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND AMIDATION AT HIS-45.
RC TISSUE=Venom gland;
RX PubMed=7759523; DOI=10.1074/jbc.270.21.12704;
RA Gmachl M., Kreil G.;
RT "The precursors of the bee venom constituents apamin and MCD peptide are
RT encoded by two genes in tandem which share the same 3'-exon.";
RL J. Biol. Chem. 270:12704-12708(1995).
RN [2]
RP PROTEIN SEQUENCE OF 28-45, SUBUNIT, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=5601655;
RA Haux P., Sawerthal H., Habermann E.;
RT "Sequence analysis of bee venom neurotoxin (apamine) from its tryptic and
RT chymotryptic cleavage products.";
RL Hoppe-Seyler's Z. Physiol. Chem. 348:737-738(1967).
RN [3]
RP PROTEIN SEQUENCE OF 28-45, SUBUNIT, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RA Shipolini R., Bradbury A.F., Callewaert G.L., Vernon C.A.;
RL J. Chem. Soc. Chem. Commun. 1967:679-680(1967).
RN [4]
RP TOXIC DOSE.
RX PubMed=1248464; DOI=10.1111/j.1432-1033.1976.tb10030.x;
RA Gauldie J., Hanson J.M., Rumjanek F.D., Shipolini R.A., Vernon C.A.;
RT "The peptide components of bee venom.";
RL Eur. J. Biochem. 61:369-376(1976).
RN [5]
RP FUNCTION, AND REGION.
RX PubMed=6122211; DOI=10.1073/pnas.79.4.1308;
RA Hugues M., Romey G., Duval D., Vincent J.P., Lazdunski M.;
RT "Apamin as a selective blocker of the calcium-dependent potassium channel
RT in neuroblastoma cells: voltage-clamp and biochemical characterization of
RT the toxin receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 79:1308-1312(1982).
RN [6]
RP FUNCTION, AND ROLE IN THE NEURODEGENERATION OF PURKINJE CELLS.
RX PubMed=9459560; DOI=10.1016/s0006-8993(97)01165-7;
RA Mourre C., Fournier C., Soumireu-Mourat B.;
RT "Apamin, a blocker of the calcium-activated potassium channel, induces
RT neurodegeneration of Purkinje cells exclusively.";
RL Brain Res. 778:405-408(1997).
RN [7]
RP FUNCTION.
RX PubMed=9287325; DOI=10.1074/jbc.272.37.23195;
RA Ishii T.M., Maylie J., Adelman J.P.;
RT "Determinants of apamin and d-tubocurarine block in SK potassium
RT channels.";
RL J. Biol. Chem. 272:23195-23200(1997).
RN [8]
RP FUNCTION.
RX PubMed=10696100; DOI=10.1038/sj.bjp.0703120;
RA Stroebaek D., Joergensen T.D., Christophersen P., Ahring P.K., Olesen S.P.;
RT "Pharmacological characterization of small-conductance Ca(2+)-activated
RT K(+) channels stably expressed in HEK 293 cells.";
RL Br. J. Pharmacol. 129:991-999(2000).
RN [9]
RP FUNCTION.
RX PubMed=11533126; DOI=10.1111/j.1469-7793.2001.00323.x;
RA Hosseini R., Benton D.C., Dunn P.M., Jenkinson D.H., Moss G.W.;
RT "SK3 is an important component of K(+) channels mediating the
RT afterhyperpolarization in cultured rat SCG neurones.";
RL J. Physiol. (Lond.) 535:323-334(2001).
RN [10]
RP FUNCTION.
RX PubMed=11212219; DOI=10.1007/s004240000447;
RA Grunnet M., Jensen B.S., Olesen S.P., Klaerke D.A.;
RT "Apamin interacts with all subtypes of cloned small-conductance Ca2+-
RT activated K+ channels.";
RL Pflugers Arch. 441:544-550(2001).
RN [11]
RP FUNCTION.
RX PubMed=17142458; DOI=10.1074/jbc.m607213200;
RA Nolting A., Ferraro T., D'hoedt D., Stocker M.;
RT "An amino acid outside the pore region influences apamin sensitivity in
RT small conductance Ca2+-activated K+ channels.";
RL J. Biol. Chem. 282:3478-3486(2007).
RN [12]
RP FUNCTION.
RX PubMed=19818752; DOI=10.1016/j.ejphar.2009.09.064;
RA de Matos Silva L.F., de Paula Ramos E.R., Ambiel C.R., Correia-de-Sa P.,
RA Alves-Do-Prado W.;
RT "Apamin reduces neuromuscular transmission by activating inhibitory
RT muscarinic M(2) receptors on motor nerve terminals.";
RL Eur. J. Pharmacol. 626:239-243(2010).
RN [13]
RP FUNCTION.
RX PubMed=20562108; DOI=10.1074/jbc.m110.110072;
RA Lamy C., Goodchild S.J., Weatherall K.L., Jane D.E., Liegeois J.F.,
RA Seutin V., Marrion N.V.;
RT "Allosteric block of KCa2 channels by apamin.";
RL J. Biol. Chem. 285:27067-27077(2010).
RN [14]
RP FUNCTION.
RX PubMed=28108814; DOI=10.1007/s00249-016-1196-0;
RA Voos P., Yazar M., Lautenschlaeger R., Rauh O., Moroni A., Thiel G.;
RT "The small neurotoxin apamin blocks not only small conductance Ca2+
RT activated K+ channels (SK type) but also the voltage dependent Kv1.3
RT channel.";
RL Eur. Biophys. J. 46:517-523(2017).
RN [15]
RP ROLE IN SUPPRESSING THE INFLAMMATORY RESPONSE.
RX PubMed=28958612; DOI=10.1016/j.pharep.2017.04.006;
RA Kim W.H., An H.J., Kim J.Y., Gwon M.G., Gu H., Lee S.J., Park J.Y.,
RA Park K.D., Han S.M., Kim M.K., Park K.K.;
RT "Apamin inhibits TNF-alpha- and IFN-gamma-induced inflammatory cytokines
RT and chemokines via suppressions of NF-kappaB signaling pathway and STAT in
RT human keratinocytes.";
RL Pharmacol. Rep. 69:1030-1035(2017).
RN [16]
RP FUNCTION, AND ROLE IN SUPPRESSING THE INFLAMMATORY RESPONSE.
RX PubMed=32560481; DOI=10.3390/ijms21124319;
RA Park J., Jang K.M., Park K.K.;
RT "Apamin Suppresses LPS-Induced Neuroinflammatory Responses by Regulating SK
RT Channels and TLR4-Mediated Signaling Pathways.";
RL Int. J. Mol. Sci. 21:0-0(2020).
RN [17]
RP ROLE IN SUPPRESSING THE INFLAMMATORY RESPONSE.
RX PubMed=32289477; DOI=10.1016/j.jep.2020.112860;
RA Lee Y.M., Cho S.N., Son E., Song C.H., Kim D.S.;
RT "Apamin from bee venom suppresses inflammation in a murine model of gouty
RT arthritis.";
RL J. Ethnopharmacol. 257:112860-112860(2020).
RN [18]
RP ROLE IN SUPPRESSING THE INFLAMMATORY RESPONSE.
RX PubMed=33287398; DOI=10.3390/molecules25235717;
RA Kim J.Y., Leem J., Park K.K.;
RT "Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a
RT Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury.";
RL Molecules 25:0-0(2020).
RN [19]
RP STRUCTURE BY NMR OF 28-45, AND DISULFIDE BOND.
RX PubMed=3242598; DOI=10.1021/bi00422a029;
RA Pease J.H.B., Wemmer D.E.;
RT "Solution structure of apamin determined by nuclear magnetic resonance and
RT distance geometry.";
RL Biochemistry 27:8491-8498(1988).
RN [20]
RP STRUCTURE BY NMR OF 28-45, AND DISULFIDE BOND.
RX PubMed=1795707;
RA Andrianov A.M., Akhrem A.A.;
RT "Spatial structure of apamin in solution.";
RL Mol. Biol. (Mosk.) 25:937-945(1991).
RN [21]
RP SYNTHESIS, ACTIVITY OF ANALOGS, AND REGION.
RX PubMed=2013287; DOI=10.1111/j.1432-1033.1991.tb15860.x;
RA Labee-Jullie C., Granier C., Alberico F., Defendini M.-L., Ceard B.,
RA Rochat H., van Rietschoten J.;
RT "Binding and toxicity of apamin. Characterization of the active site.";
RL Eur. J. Biochem. 196:639-645(1991).
CC -!- FUNCTION: Neurotoxin that blocks the small-conductance calcium-
CC activated potassium (SK) channels KCa2.1/KCNN1/SK1, KCa2.2/KCNN2/SK2
CC and KCa2.3/KCNN3/SK3 (PubMed:6122211, PubMed:9459560, PubMed:9287325,
CC PubMed:10696100, PubMed:11533126, PubMed:11212219, PubMed:17142458,
CC PubMed:20562108, PubMed:32560481). Also irreversibly blocks the
CC voltage-gated potassium channel Kv1.3/KCNA3 (IC(50)=13 nM)
CC (PubMed:28108814). Potently blocks human, rat and mouse
CC KCa2.2/KCNN2/SK2 channels (IC(50)=27-140 pM), and moderately blocks
CC human and rat KCa2.3/KCNN3/SK3 channels (IC(50)=0.6-4 nM), and human
CC (IC(50)=0.7-12 nM) and mouse (IC(50)=28 nM) KCa2.1/KCNN1/SK1 channels
CC (PubMed:9459560, PubMed:9287325, PubMed:10696100, PubMed:11533126,
CC PubMed:11212219, PubMed:17142458, PubMed:20562108). However, other
CC reports found that it did not block the human KCa2.1/KCNN1/SK1 channels
CC (PubMed:9287325). Also able to inhibit neuromuscular transmission by a
CC mechanism independent of the blockade of SK channels, which may involve
CC the activation of inhibitory muscarinic M2 receptors on motor nerve
CC terminals (PubMed:19818752). {ECO:0000269|PubMed:10696100,
CC ECO:0000269|PubMed:11212219, ECO:0000269|PubMed:11533126,
CC ECO:0000269|PubMed:17142458, ECO:0000269|PubMed:19818752,
CC ECO:0000269|PubMed:20562108, ECO:0000269|PubMed:28108814,
CC ECO:0000269|PubMed:32560481, ECO:0000269|PubMed:6122211,
CC ECO:0000269|PubMed:9287325, ECO:0000269|PubMed:9459560}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:5601655,
CC ECO:0000269|Ref.3}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:7759523}.
CC -!- TOXIC DOSE: LD(50) is 3-5 mg/ kg by intravenous injection into mice.
CC {ECO:0000269|PubMed:1248464}.
CC -!- MISCELLANEOUS: When administered at high doses, exerts anti-
CC inflammatory, anti-oxidative, anti-fibrotic and anti-apoptotic
CC properties in several models of inflammatory disease, including gouty
CC arthritis, atherosclerosis, atopic dermatitis and acute kidney injury
CC (PubMed:28958612, PubMed:32560481, PubMed:33287398, PubMed:32289477).
CC Down-regulates pro-inflammatory signaling pathways, such as the NF-
CC kappaB and STAT3 pathways, probably by blocking SK channels such as
CC KCa2.2/KCNN2/SK2 and/or KCa2.3/KCNN3/SK3 which are thought to be
CC involved in promoting some inflammatory responses (PubMed:28958612,
CC PubMed:32560481, PubMed:33287398, PubMed:32289477). For example in
CC mouse and rat microglia cells, inhibits LPS-activated KCa2.2/KCNN2/SK2
CC channels and TLR4 expression leading to the down-regulation of the NF-
CC kappaB, STAT, and MAPK/ERK signaling pathways and, as a consequence,
CC decreases secretion of pro-inflammatory cytokines (PubMed:32560481).
CC {ECO:0000269|PubMed:28958612, ECO:0000269|PubMed:32289477,
CC ECO:0000269|PubMed:32560481, ECO:0000269|PubMed:33287398}.
CC -!- MISCELLANEOUS: In rats, a dose of 1 ng results in neurodegeneration
CC specifically in the Purkinje cells of the cerebellum, and induces
CC seizures characterized by hypersensitivity to noise, loss of postural
CC control, paroxystic jerking, and alternating periods of great agitation
CC with tonic-clonic convulsions and periods of total prostration.
CC {ECO:0000269|PubMed:9459560}.
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DR EMBL; S78458; AAB34402.1; -; mRNA.
DR PIR; A56710; AMHB.
DR RefSeq; NP_001011612.1; NM_001011612.1.
DR AlphaFoldDB; P01500; -.
DR BMRB; P01500; -.
DR SMR; P01500; -.
DR STRING; 7460.GB40697-PA; -.
DR PaxDb; P01500; -.
DR EnsemblMetazoa; NM_001011612; NP_001011612; GeneID_406135.
DR GeneID; 406135; -.
DR KEGG; ame:406135; -.
DR CTD; 406135; -.
DR HOGENOM; CLU_214040_0_0_1; -.
DR Proteomes; UP000005203; Unplaced.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0070320; F:inward rectifier potassium channel inhibitor activity; IDA:UniProtKB.
DR GO; GO:0019870; F:potassium channel inhibitor activity; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0035821; P:modulation of process of another organism; IDA:UniProtKB.
DR GO; GO:1903609; P:negative regulation of inward rectifier potassium channel activity; IDA:UniProtKB.
DR GO; GO:1901380; P:negative regulation of potassium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:1901017; P:negative regulation of potassium ion transmembrane transporter activity; IDA:UniProtKB.
DR InterPro; IPR035361; Bee_toxin.
DR Pfam; PF17454; Bee_toxin; 1.
PE 1: Evidence at protein level;
KW Amidation; Calcium-activated potassium channel impairing toxin;
KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin;
KW Neurotoxin; Potassium channel impairing toxin; Reference proteome;
KW Secreted; Signal; Toxin; Voltage-gated potassium channel impairing toxin.
FT SIGNAL 1..27
FT /evidence="ECO:0000269|PubMed:5601655, ECO:0000269|Ref.3"
FT PEPTIDE 28..45
FT /note="Apamin"
FT /evidence="ECO:0000269|PubMed:5601655, ECO:0000269|Ref.3"
FT /id="PRO_0000018611"
FT REGION 40..41
FT /note="Essential for toxin activity"
FT /evidence="ECO:0000269|PubMed:2013287,
FT ECO:0000269|PubMed:6122211"
FT MOD_RES 45
FT /note="Histidine amide"
FT /evidence="ECO:0000305|PubMed:7759523"
FT DISULFID 28..38
FT /evidence="ECO:0000269|PubMed:1795707,
FT ECO:0000269|PubMed:3242598"
FT DISULFID 30..42
FT /evidence="ECO:0000269|PubMed:1795707,
FT ECO:0000269|PubMed:3242598"
SQ SEQUENCE 46 AA; 5223 MW; 92694A07501AEE33 CRC64;
MISMLRCIYL FLSVILITSY FVTPVMPCNC KAPETALCAR RCQQHG
