Full text data of KCNN4
KCNN4
(IK1, IKCA1, KCA4, SK4)
[Confidence: high (present in two of the MS resources)]
Intermediate conductance calcium-activated potassium channel protein 4; SK4; SKCa 4; SKCa4 (IKCa1; IK1; KCa3.1; KCa4; Putative Gardos channel)
Intermediate conductance calcium-activated potassium channel protein 4; SK4; SKCa 4; SKCa4 (IKCa1; IK1; KCa3.1; KCa4; Putative Gardos channel)
hRBCD
IPI00032466
IPI00032466 Intermediate conductance calcium-activated potassium channel protein 4 Intermediate conductance calcium-activated potassium channel protein 4 membrane n/a 1 4 2 3 1 3 n/a n/a n/a 4 3 n/a 3 1 n/a n/a n/a 1 n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight
IPI00032466 Intermediate conductance calcium-activated potassium channel protein 4 Intermediate conductance calcium-activated potassium channel protein 4 membrane n/a 1 4 2 3 1 3 n/a n/a n/a 4 3 n/a 3 1 n/a n/a n/a 1 n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight
UniProt
O15554
ID KCNN4_HUMAN Reviewed; 427 AA.
AC O15554; Q53XR4;
DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1998, sequence version 1.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Intermediate conductance calcium-activated potassium channel protein 4;
DE Short=SK4;
DE Short=SKCa 4;
DE Short=SKCa4;
DE AltName: Full=IKCa1;
DE Short=IK1;
DE AltName: Full=KCa3.1;
DE AltName: Full=KCa4;
DE AltName: Full=Putative Gardos channel;
GN Name=KCNN4; Synonyms=IK1, IKCA1, KCA4, SK4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=9380751; DOI=10.1073/pnas.94.20.11013;
RA Joiner W.J., Wang L.-Y., Tang M.D., Kaczmarek L.K.;
RT "hSK4, a member of a novel subfamily of calcium-activated potassium
RT channels.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:11013-11018(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Pancreas;
RX PubMed=9326665; DOI=10.1073/pnas.94.21.11651;
RA Ishii T.M., Silvia C., Hirschberg B., Bond C.T., Adelman J.P.,
RA Maylie J.;
RT "A human intermediate conductance calcium-activated potassium
RT channel.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:11651-11656(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lymph node;
RX PubMed=9407042; DOI=10.1074/jbc.272.52.32723;
RA Logsdon N.J., Kang J., Togo J.A., Christian E.P., Aiyar J.;
RT "A novel gene, hKCa4, encodes the calcium-activated potassium channel
RT in human T lymphocytes.";
RL J. Biol. Chem. 272:32723-32726(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9693050; DOI=10.1006/geno.1998.5333;
RA Ghanshani S., Coleman M., Gustavsson P., Wu A.C., Gargus J.J.,
RA Gutman G.A., Dahl N., Mohrenweiser H., Chandy K.G.;
RT "Human calcium-activated potassium channel gene KCNN4 maps to
RT chromosome 19q13.2 in the region deleted in diamond-blackfan anemia.";
RL Genomics 51:160-161(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10961988; DOI=10.1074/jbc.M003941200;
RA Ghanshani S., Wulff H., Miller M.J., Rohm H., Neben A., Gutman G.A.,
RA Cahalan M.D., Chandy K.G.;
RT "Up-regulation of the IKCa1 potassium channel during T-cell
RT activation. Molecular mechanism and functional consequences.";
RL J. Biol. Chem. 275:37137-37149(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Myometrium;
RA Mazzone J.N., Kaiser R.A., Buxton I.L.O.;
RT "Characterization of calcium-activated potassium channels in human
RT myometrium.";
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 227-367.
RA Golding S., Culliford S.J., Ellory J.C.;
RT "hIK1 (putative Gardos channel) PCR product amplified from the K562
RT human erythroleukemic cell line.";
RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP INTERACTION WITH CALMODULIN.
RX PubMed=10026195; DOI=10.1074/jbc.274.9.5746;
RA Fanger C.M., Ghanshani S., Logsdon N.J., Rauer H., Kalman K., Zhou J.,
RA Beckingham K., Chandy K.G., Cahalan M.D., Aiyar J.;
RT "Calmodulin mediates calcium-dependent activation of the intermediate
RT conductance KCa channel, IKCa1.";
RL J. Biol. Chem. 274:5746-5754(1999).
RN [12]
RP MUTAGENESIS OF THR-250 AND VAL-275.
RX PubMed=11425865; DOI=10.1074/jbc.M105231200;
RA Wulff H., Gutman G.A., Cahalan M.D., Chandy K.G.;
RT "Delineation of the clotrimazole/TRAM-34 binding site on the
RT intermediate conductance calcium-activated potassium channel, IKCa1.";
RL J. Biol. Chem. 276:32040-32045(2001).
RN [13]
RP INTERACTION WITH MTMR6.
RX PubMed=15831468; DOI=10.1128/MCB.25.9.3630-3638.2005;
RA Srivastava S., Li Z., Lin L., Liu G., Ko K., Coetzee W.A.,
RA Skolnik E.Y.;
RT "The phosphatidylinositol 3-phosphate phosphatase myotubularin-related
RT protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+
RT channel KCa3.1.";
RL Mol. Cell. Biol. 25:3630-3638(2005).
RN [14]
RP FUNCTION, AND PHOSPHORYLATION AT HIS-358.
RX PubMed=17157250; DOI=10.1016/j.molcel.2006.11.012;
RA Srivastava S., Li Z., Ko K., Choudhury P., Albaqumi M., Johnson A.K.,
RA Yan Y., Backer J.M., Unutmaz D., Coetzee W.A., Skolnik E.Y.;
RT "Histidine phosphorylation of the potassium channel KCa3.1 by
RT nucleoside diphosphate kinase B is required for activation of KCa3.1
RT and CD4 T cells.";
RL Mol. Cell 24:665-675(2006).
RN [15]
RP FUNCTION, AND INHIBITIVE DEPHOSPHORYLATION BY PTHP1.
RX PubMed=18796614; DOI=10.1073/pnas.0803678105;
RA Srivastava S., Zhdanova O., Di L., Li Z., Albaqumi M., Wulff H.,
RA Skolnik E.Y.;
RT "Protein histidine phosphatase 1 negatively regulates CD4 T cells by
RT inhibiting the K+ channel KCa3.1.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:14442-14446(2008).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Forms a voltage-independent potassium channel that is
CC activated by intracellular calcium. Activation is followed by
CC membrane hyperpolarization which promotes calcium influx. Required
CC for maximal calcium influx and proliferation during the
CC reactivation of naive T-cells. The channel is blocked by
CC clotrimazole and charybdotoxin but is insensitive to apamin.
CC -!- SUBUNIT: Heterotetramer of potassium channel proteins (Probable).
CC Interacts with MTMR6.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Widely expressed in non-excitable tissues.
CC -!- INDUCTION: Up-regulated by phorbol myristate acetate (PMA) and
CC phytohemagglutinin (PHA) in T-cells.
CC -!- PTM: Phosphorylation at His-358 by NDKB activates the channel, and
CC conversely it's dephosphorylation by PHPT1 inhibits the channel.
CC -!- SIMILARITY: Belongs to the potassium channel KCNN family.
CC KCa3.1/KCNN4 subfamily.
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DR EMBL; AF000972; AAB82739.1; -; mRNA.
DR EMBL; AF022150; AAC23541.1; -; mRNA.
DR EMBL; AF022797; AAC51913.1; -; mRNA.
DR EMBL; AF033021; AAC36804.1; -; mRNA.
DR EMBL; AF305735; AAG26917.1; -; Genomic_DNA.
DR EMBL; AF305731; AAG26917.1; JOINED; Genomic_DNA.
DR EMBL; AF305732; AAG26917.1; JOINED; Genomic_DNA.
DR EMBL; AF305733; AAG26917.1; JOINED; Genomic_DNA.
DR EMBL; AF305734; AAG26917.1; JOINED; Genomic_DNA.
DR EMBL; AF395661; AAK81862.1; -; mRNA.
DR EMBL; BT007426; AAP36094.1; -; mRNA.
DR EMBL; CH471126; EAW57230.1; -; Genomic_DNA.
DR EMBL; BC015337; AAH15337.1; -; mRNA.
DR EMBL; AF053403; AAC35281.1; -; mRNA.
DR RefSeq; NP_002241.1; NM_002250.2.
DR UniGene; Hs.10082; -.
DR ProteinModelPortal; O15554; -.
DR SMR; O15554; 287-373.
DR DIP; DIP-48598N; -.
DR IntAct; O15554; 1.
DR STRING; 9606.ENSP00000262888; -.
DR BindingDB; O15554; -.
DR ChEMBL; CHEMBL4305; -.
DR DrugBank; DB00257; Clotrimazole.
DR DrugBank; DB01159; Halothane.
DR DrugBank; DB00468; Quinine.
DR GuidetoPHARMACOLOGY; 384; -.
DR TCDB; 1.A.1.16.2; the voltage-gated ion channel (vic) superfamily.
DR PhosphoSite; O15554; -.
DR PaxDb; O15554; -.
DR PRIDE; O15554; -.
DR DNASU; 3783; -.
DR Ensembl; ENST00000262888; ENSP00000262888; ENSG00000104783.
DR GeneID; 3783; -.
DR KEGG; hsa:3783; -.
DR UCSC; uc002oxl.3; human.
DR CTD; 3783; -.
DR GeneCards; GC19M044270; -.
DR HGNC; HGNC:6293; KCNN4.
DR MIM; 602754; gene.
DR neXtProt; NX_O15554; -.
DR PharmGKB; PA222; -.
DR eggNOG; NOG323309; -.
DR HOGENOM; HOG000276908; -.
DR HOVERGEN; HBG052241; -.
DR InParanoid; O15554; -.
DR KO; K04945; -.
DR OMA; CMISIST; -.
DR PhylomeDB; O15554; -.
DR Reactome; REACT_13685; Neuronal System.
DR GeneWiki; KCNN4; -.
DR GenomeRNAi; 3783; -.
DR NextBio; 14849; -.
DR PRO; PR:O15554; -.
DR ArrayExpress; O15554; -.
DR Bgee; O15554; -.
DR CleanEx; HS_KCNN4; -.
DR Genevestigator; O15554; -.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; IC:BHF-UCL.
DR GO; GO:0015269; F:calcium-activated potassium channel activity; IDA:BHF-UCL.
DR GO; GO:0016286; F:small conductance calcium-activated potassium channel activity; IEA:InterPro.
DR GO; GO:0006816; P:calcium ion transport; IDA:BHF-UCL.
DR GO; GO:0006884; P:cell volume homeostasis; IEA:Ensembl.
DR GO; GO:0006952; P:defense response; TAS:ProtInc.
DR GO; GO:0045332; P:phospholipid translocation; IEA:Ensembl.
DR GO; GO:0050714; P:positive regulation of protein secretion; IEA:Ensembl.
DR GO; GO:0050862; P:positive regulation of T cell receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0046541; P:saliva secretion; IEA:Ensembl.
DR GO; GO:0030322; P:stabilization of membrane potential; IDA:BHF-UCL.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR InterPro; IPR013099; 2pore_dom_K_chnl_dom.
DR InterPro; IPR004178; CaM-bd_dom.
DR InterPro; IPR015449; K_chnl_Ca-activ_SK.
DR PANTHER; PTHR10153; PTHR10153; 1.
DR Pfam; PF02888; CaMBD; 1.
DR Pfam; PF07885; Ion_trans_2; 1.
DR Pfam; PF03530; SK_channel; 1.
DR SMART; SM01053; CaMBD; 1.
DR SUPFAM; SSF81327; SSF81327; 1.
PE 1: Evidence at protein level;
KW Calmodulin-binding; Complete proteome; Immunity; Ion channel;
KW Ion transport; Membrane; Phosphoprotein; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 427 Intermediate conductance calcium-
FT activated potassium channel protein 4.
FT /FTId=PRO_0000155017.
FT TRANSMEM 29 49 Helical; Name=Segment S1; (Potential).
FT TRANSMEM 59 79 Helical; Name=Segment S2; (Potential).
FT TRANSMEM 108 128 Helical; Name=Segment S3; (Potential).
FT TRANSMEM 143 163 Helical; Name=Segment S4; (Potential).
FT TRANSMEM 207 227 Helical; Name=Segment S5; (Potential).
FT INTRAMEM 241 261 Pore-forming; Name=Segment H5;
FT (Potential).
FT TRANSMEM 265 285 Helical; Name=Segment S6; (Potential).
FT REGION 286 347 Calmodulin-binding.
FT MOD_RES 358 358 Phosphohistidine.
FT MUTAGEN 250 250 T->S: Loss of sensitivity to
FT triarylmethanes.
FT MUTAGEN 275 275 V->A: Loss of sensitivity to
FT triarylmethanes.
FT CONFLICT 66 66 S -> G (in Ref. 6; AAK81862).
SQ SEQUENCE 427 AA; 47696 MW; 23F9AF66609B410F CRC64;
MGGDLVLGLG ALRRRKRLLE QEKSLAGWAL VLAGTGIGLM VLHAEMLWFG GCSWALYLFL
VKCTISISTF LLLCLIVAFH AKEVQLFMTD NGLRDWRVAL TGRQAAQIVL ELVVCGLHPA
PVRGPPCVQD LGAPLTSPQP WPGFLGQGEA LLSLAMLLRL YLVPRAVLLR SGVLLNASYR
SIGALNQVRF RHWFVAKLYM NTHPGRLLLG LTLGLWLTTA WVLSVAERQA VNATGHLSDT
LWLIPITFLT IGYGDVVPGT MWGKIVCLCT GVMGVCCTAL LVAVVARKLE FNKAEKHVHN
FMMDIQYTKE MKESAARVLQ EAWMFYKHTR RKESHAARRH QRKLLAAINA FRQVRLKHRK
LREQVNSMVD ISKMHMILYD LQQNLSSSHR ALEKQIDTLA GKLDALTELL STALGPRQLP
EPSQQSK
//
ID KCNN4_HUMAN Reviewed; 427 AA.
AC O15554; Q53XR4;
DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1998, sequence version 1.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Intermediate conductance calcium-activated potassium channel protein 4;
DE Short=SK4;
DE Short=SKCa 4;
DE Short=SKCa4;
DE AltName: Full=IKCa1;
DE Short=IK1;
DE AltName: Full=KCa3.1;
DE AltName: Full=KCa4;
DE AltName: Full=Putative Gardos channel;
GN Name=KCNN4; Synonyms=IK1, IKCA1, KCA4, SK4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=9380751; DOI=10.1073/pnas.94.20.11013;
RA Joiner W.J., Wang L.-Y., Tang M.D., Kaczmarek L.K.;
RT "hSK4, a member of a novel subfamily of calcium-activated potassium
RT channels.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:11013-11018(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Pancreas;
RX PubMed=9326665; DOI=10.1073/pnas.94.21.11651;
RA Ishii T.M., Silvia C., Hirschberg B., Bond C.T., Adelman J.P.,
RA Maylie J.;
RT "A human intermediate conductance calcium-activated potassium
RT channel.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:11651-11656(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lymph node;
RX PubMed=9407042; DOI=10.1074/jbc.272.52.32723;
RA Logsdon N.J., Kang J., Togo J.A., Christian E.P., Aiyar J.;
RT "A novel gene, hKCa4, encodes the calcium-activated potassium channel
RT in human T lymphocytes.";
RL J. Biol. Chem. 272:32723-32726(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9693050; DOI=10.1006/geno.1998.5333;
RA Ghanshani S., Coleman M., Gustavsson P., Wu A.C., Gargus J.J.,
RA Gutman G.A., Dahl N., Mohrenweiser H., Chandy K.G.;
RT "Human calcium-activated potassium channel gene KCNN4 maps to
RT chromosome 19q13.2 in the region deleted in diamond-blackfan anemia.";
RL Genomics 51:160-161(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10961988; DOI=10.1074/jbc.M003941200;
RA Ghanshani S., Wulff H., Miller M.J., Rohm H., Neben A., Gutman G.A.,
RA Cahalan M.D., Chandy K.G.;
RT "Up-regulation of the IKCa1 potassium channel during T-cell
RT activation. Molecular mechanism and functional consequences.";
RL J. Biol. Chem. 275:37137-37149(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Myometrium;
RA Mazzone J.N., Kaiser R.A., Buxton I.L.O.;
RT "Characterization of calcium-activated potassium channels in human
RT myometrium.";
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 227-367.
RA Golding S., Culliford S.J., Ellory J.C.;
RT "hIK1 (putative Gardos channel) PCR product amplified from the K562
RT human erythroleukemic cell line.";
RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP INTERACTION WITH CALMODULIN.
RX PubMed=10026195; DOI=10.1074/jbc.274.9.5746;
RA Fanger C.M., Ghanshani S., Logsdon N.J., Rauer H., Kalman K., Zhou J.,
RA Beckingham K., Chandy K.G., Cahalan M.D., Aiyar J.;
RT "Calmodulin mediates calcium-dependent activation of the intermediate
RT conductance KCa channel, IKCa1.";
RL J. Biol. Chem. 274:5746-5754(1999).
RN [12]
RP MUTAGENESIS OF THR-250 AND VAL-275.
RX PubMed=11425865; DOI=10.1074/jbc.M105231200;
RA Wulff H., Gutman G.A., Cahalan M.D., Chandy K.G.;
RT "Delineation of the clotrimazole/TRAM-34 binding site on the
RT intermediate conductance calcium-activated potassium channel, IKCa1.";
RL J. Biol. Chem. 276:32040-32045(2001).
RN [13]
RP INTERACTION WITH MTMR6.
RX PubMed=15831468; DOI=10.1128/MCB.25.9.3630-3638.2005;
RA Srivastava S., Li Z., Lin L., Liu G., Ko K., Coetzee W.A.,
RA Skolnik E.Y.;
RT "The phosphatidylinositol 3-phosphate phosphatase myotubularin-related
RT protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+
RT channel KCa3.1.";
RL Mol. Cell. Biol. 25:3630-3638(2005).
RN [14]
RP FUNCTION, AND PHOSPHORYLATION AT HIS-358.
RX PubMed=17157250; DOI=10.1016/j.molcel.2006.11.012;
RA Srivastava S., Li Z., Ko K., Choudhury P., Albaqumi M., Johnson A.K.,
RA Yan Y., Backer J.M., Unutmaz D., Coetzee W.A., Skolnik E.Y.;
RT "Histidine phosphorylation of the potassium channel KCa3.1 by
RT nucleoside diphosphate kinase B is required for activation of KCa3.1
RT and CD4 T cells.";
RL Mol. Cell 24:665-675(2006).
RN [15]
RP FUNCTION, AND INHIBITIVE DEPHOSPHORYLATION BY PTHP1.
RX PubMed=18796614; DOI=10.1073/pnas.0803678105;
RA Srivastava S., Zhdanova O., Di L., Li Z., Albaqumi M., Wulff H.,
RA Skolnik E.Y.;
RT "Protein histidine phosphatase 1 negatively regulates CD4 T cells by
RT inhibiting the K+ channel KCa3.1.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:14442-14446(2008).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Forms a voltage-independent potassium channel that is
CC activated by intracellular calcium. Activation is followed by
CC membrane hyperpolarization which promotes calcium influx. Required
CC for maximal calcium influx and proliferation during the
CC reactivation of naive T-cells. The channel is blocked by
CC clotrimazole and charybdotoxin but is insensitive to apamin.
CC -!- SUBUNIT: Heterotetramer of potassium channel proteins (Probable).
CC Interacts with MTMR6.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Widely expressed in non-excitable tissues.
CC -!- INDUCTION: Up-regulated by phorbol myristate acetate (PMA) and
CC phytohemagglutinin (PHA) in T-cells.
CC -!- PTM: Phosphorylation at His-358 by NDKB activates the channel, and
CC conversely it's dephosphorylation by PHPT1 inhibits the channel.
CC -!- SIMILARITY: Belongs to the potassium channel KCNN family.
CC KCa3.1/KCNN4 subfamily.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; AF000972; AAB82739.1; -; mRNA.
DR EMBL; AF022150; AAC23541.1; -; mRNA.
DR EMBL; AF022797; AAC51913.1; -; mRNA.
DR EMBL; AF033021; AAC36804.1; -; mRNA.
DR EMBL; AF305735; AAG26917.1; -; Genomic_DNA.
DR EMBL; AF305731; AAG26917.1; JOINED; Genomic_DNA.
DR EMBL; AF305732; AAG26917.1; JOINED; Genomic_DNA.
DR EMBL; AF305733; AAG26917.1; JOINED; Genomic_DNA.
DR EMBL; AF305734; AAG26917.1; JOINED; Genomic_DNA.
DR EMBL; AF395661; AAK81862.1; -; mRNA.
DR EMBL; BT007426; AAP36094.1; -; mRNA.
DR EMBL; CH471126; EAW57230.1; -; Genomic_DNA.
DR EMBL; BC015337; AAH15337.1; -; mRNA.
DR EMBL; AF053403; AAC35281.1; -; mRNA.
DR RefSeq; NP_002241.1; NM_002250.2.
DR UniGene; Hs.10082; -.
DR ProteinModelPortal; O15554; -.
DR SMR; O15554; 287-373.
DR DIP; DIP-48598N; -.
DR IntAct; O15554; 1.
DR STRING; 9606.ENSP00000262888; -.
DR BindingDB; O15554; -.
DR ChEMBL; CHEMBL4305; -.
DR DrugBank; DB00257; Clotrimazole.
DR DrugBank; DB01159; Halothane.
DR DrugBank; DB00468; Quinine.
DR GuidetoPHARMACOLOGY; 384; -.
DR TCDB; 1.A.1.16.2; the voltage-gated ion channel (vic) superfamily.
DR PhosphoSite; O15554; -.
DR PaxDb; O15554; -.
DR PRIDE; O15554; -.
DR DNASU; 3783; -.
DR Ensembl; ENST00000262888; ENSP00000262888; ENSG00000104783.
DR GeneID; 3783; -.
DR KEGG; hsa:3783; -.
DR UCSC; uc002oxl.3; human.
DR CTD; 3783; -.
DR GeneCards; GC19M044270; -.
DR HGNC; HGNC:6293; KCNN4.
DR MIM; 602754; gene.
DR neXtProt; NX_O15554; -.
DR PharmGKB; PA222; -.
DR eggNOG; NOG323309; -.
DR HOGENOM; HOG000276908; -.
DR HOVERGEN; HBG052241; -.
DR InParanoid; O15554; -.
DR KO; K04945; -.
DR OMA; CMISIST; -.
DR PhylomeDB; O15554; -.
DR Reactome; REACT_13685; Neuronal System.
DR GeneWiki; KCNN4; -.
DR GenomeRNAi; 3783; -.
DR NextBio; 14849; -.
DR PRO; PR:O15554; -.
DR ArrayExpress; O15554; -.
DR Bgee; O15554; -.
DR CleanEx; HS_KCNN4; -.
DR Genevestigator; O15554; -.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; IC:BHF-UCL.
DR GO; GO:0015269; F:calcium-activated potassium channel activity; IDA:BHF-UCL.
DR GO; GO:0016286; F:small conductance calcium-activated potassium channel activity; IEA:InterPro.
DR GO; GO:0006816; P:calcium ion transport; IDA:BHF-UCL.
DR GO; GO:0006884; P:cell volume homeostasis; IEA:Ensembl.
DR GO; GO:0006952; P:defense response; TAS:ProtInc.
DR GO; GO:0045332; P:phospholipid translocation; IEA:Ensembl.
DR GO; GO:0050714; P:positive regulation of protein secretion; IEA:Ensembl.
DR GO; GO:0050862; P:positive regulation of T cell receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0046541; P:saliva secretion; IEA:Ensembl.
DR GO; GO:0030322; P:stabilization of membrane potential; IDA:BHF-UCL.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR InterPro; IPR013099; 2pore_dom_K_chnl_dom.
DR InterPro; IPR004178; CaM-bd_dom.
DR InterPro; IPR015449; K_chnl_Ca-activ_SK.
DR PANTHER; PTHR10153; PTHR10153; 1.
DR Pfam; PF02888; CaMBD; 1.
DR Pfam; PF07885; Ion_trans_2; 1.
DR Pfam; PF03530; SK_channel; 1.
DR SMART; SM01053; CaMBD; 1.
DR SUPFAM; SSF81327; SSF81327; 1.
PE 1: Evidence at protein level;
KW Calmodulin-binding; Complete proteome; Immunity; Ion channel;
KW Ion transport; Membrane; Phosphoprotein; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 427 Intermediate conductance calcium-
FT activated potassium channel protein 4.
FT /FTId=PRO_0000155017.
FT TRANSMEM 29 49 Helical; Name=Segment S1; (Potential).
FT TRANSMEM 59 79 Helical; Name=Segment S2; (Potential).
FT TRANSMEM 108 128 Helical; Name=Segment S3; (Potential).
FT TRANSMEM 143 163 Helical; Name=Segment S4; (Potential).
FT TRANSMEM 207 227 Helical; Name=Segment S5; (Potential).
FT INTRAMEM 241 261 Pore-forming; Name=Segment H5;
FT (Potential).
FT TRANSMEM 265 285 Helical; Name=Segment S6; (Potential).
FT REGION 286 347 Calmodulin-binding.
FT MOD_RES 358 358 Phosphohistidine.
FT MUTAGEN 250 250 T->S: Loss of sensitivity to
FT triarylmethanes.
FT MUTAGEN 275 275 V->A: Loss of sensitivity to
FT triarylmethanes.
FT CONFLICT 66 66 S -> G (in Ref. 6; AAK81862).
SQ SEQUENCE 427 AA; 47696 MW; 23F9AF66609B410F CRC64;
MGGDLVLGLG ALRRRKRLLE QEKSLAGWAL VLAGTGIGLM VLHAEMLWFG GCSWALYLFL
VKCTISISTF LLLCLIVAFH AKEVQLFMTD NGLRDWRVAL TGRQAAQIVL ELVVCGLHPA
PVRGPPCVQD LGAPLTSPQP WPGFLGQGEA LLSLAMLLRL YLVPRAVLLR SGVLLNASYR
SIGALNQVRF RHWFVAKLYM NTHPGRLLLG LTLGLWLTTA WVLSVAERQA VNATGHLSDT
LWLIPITFLT IGYGDVVPGT MWGKIVCLCT GVMGVCCTAL LVAVVARKLE FNKAEKHVHN
FMMDIQYTKE MKESAARVLQ EAWMFYKHTR RKESHAARRH QRKLLAAINA FRQVRLKHRK
LREQVNSMVD ISKMHMILYD LQQNLSSSHR ALEKQIDTLA GKLDALTELL STALGPRQLP
EPSQQSK
//
MIM
602754
*RECORD*
*FIELD* NO
602754
*FIELD* TI
*602754 POTASSIUM CHANNEL, CALCIUM-ACTIVATED, INTERMEDIATE/SMALL CONDUCTANCE,
SUBFAMILY N, MEMBER 4; KCNN4
read more;;IK1;;
SK4;;
KCA4;;
KCA3.1
*FIELD* TX
DESCRIPTION
The calcium-activated potassium channels (KCa channels) have been
classified into 3 groups. Large conductance (BK) channels are gated by
the concerted actions of internal calcium ions and membrane potential
and have a unit conductance of 100 to 220 picoSiemens (pS). Intermediate
conductance (IK) and small conductance (SK) channels are gated solely by
internal calcium ions, with a unit conductance of 20 to 85 pS and 2 to
20 pS, respectively, and are more sensitive to calcium than are BK
channels. Each type of channel shows a distinct pharmacology. KCNN4
belongs to a family of IK and SK channels (Ishii et al., 1997).
CLONING
Joiner et al. (1997) cloned cDNAs encoding KCNN4, which they called SK4.
The predicted 427-amino acid sequence of KCNN4 was approximately 40%
identical to that of the rat and human SK channel proteins rSK1, rSK2,
rSK3 and hSK1. Sequence analysis revealed that, like the SK channel
proteins, KCNN4 contained 6 putative transmembrane domains, a conserved
pore region, and a leucine zipper-like motif near the C terminus. By
Northern analysis, the authors found that KCNN4 was expressed as 2.6-kb
and 3.8-kb transcripts in placenta and at lower levels in lung and
pancreas. Joiner et al. (1997) proposed that KCNN4 belongs to a novel
subfamily of SK channels.
Ishii et al. (1997) also identified a cDNA encoding KCNN4, called IK1 by
them. They classified KCNN4 as an IK channel based on its physiologic
properties.
Independently, Logsdon et al. (1997) isolated a human lymph node cDNA
encoding KCNN4, which they called KCa4. Northern analysis revealed that
KCNN4 was expressed predominantly as a 2.2-kb mRNA in a variety of
tissues, with minor larger transcripts in some tissues. Logsdon et al.
(1997) found that the 2.2-kb KCNN4 transcript was 10-fold more abundant
in activated T cells than in resting T cells, concomitant with an
increase in the KCa channel current.
GENE FUNCTION
Joiner et al. (1997) found that KCNN4 generated a conductance of
approximately 12 pS and had a very high affinity for calcium when
expressed in Chinese hamster ovary cells. They concluded that KCNN4 is a
novel SK channel.
Ishii et al. (1997) classified KCNN4 as an IK channel because its
expression in Xenopus oocytes produced potassium channels with a
conductance level of 39 pS that showed the biophysical and pharmacologic
properties of native IK channels.
Logsdon et al. (1997) found that expression of KCNN4 in mammalian cells
produced channels having a conductance of 33 pS, with electrophysiologic
properties that were very similar to those reported for the native KCa
channel in activated human T lymphocytes. Logsdon et al. (1997)
suggested that KCNN4 encodes the predominant KCa channel in T
lymphocytes.
Hoffman et al. (2003) presented evidence that KCNN4 is the gene that
codes for the Ca(2+)-activated K(+) channel (Gardos channel) in red
blood cells. This channel is important pathophysiologically, because it
represents the major pathway for cell shrinkage via KCl and water loss
that occurs in sickle cell disease (603903).
Cheong et al. (2005) identified a functional REST (600571)-binding
sequence in the promoter region of the KCNN4 gene. REST was expressed in
the nuclei of human vascular smooth muscle cells (SMCs), and it
downregulated KCNN4 expression in mouse and human vascular SMCs.
Downregulated REST and upregulated KCNN4 were evident in SMCs of human
neointimal hyperplasia grown in organ culture, and exogenous REST
reduced the functional impact of KCNN4. Cheong et al. (2005) concluded
that REST acts as a switch to regulate potassium channel expression and
consequently the phenotype of vascular smooth muscle cells and human
vascular disease.
Srivastava et al. (2006) demonstrated that the 14 C-terminal amino acids
of KCa3.1 that mediate the regulation of KCa3.1 by phosphatidylinositol
3-phosphate (PI(3)P) recruit NDPKB (156491) to KCa3.1. NDPKB then
activates KCa3.1 by phosphorylating residue H358, which is present in
the same C-terminal 14-amino acid region. SiRNA treatment of NDPBK in
CD4+ T cells resulted in a marked reduction of KCa3.1 channel activity.
Srivastava et al. (2006) concluded that histidine phosphorylation
regulates KCa3.1 channel activity and that NDPBK is critical to the
channel activity and the activation of CD4 T cells.
Toyama et al. (2008) found that coronary vessels from patients with
coronary artery disease expressed elevated levels of KCa3.1.
Pharmacologic blockade and gene silencing of KCa3.1 in human vascular
smooth muscle cells (VSMCs) suppressed proliferation, migration, and
oxidative stress. In Apoe (107741) -/- mice, a genetic model of
atherosclerosis, KCa3.1 expression was elevated in VSMCs, macrophages,
and T lymphocytes that infiltrated atherosclerotic lesions, whereas VSMC
proliferation and macrophage activation was reduced. Long-term KCa3.1
blockade reduced the development of atherosclerosis in aortas of Apoe
-/- mice by suppressing VSMC proliferation and migration into plaques,
decreasing infiltration of plaques by macrophages and T lymphocytes, and
reducing oxidative stress.
Grgic et al. (2009) found that stimulation of mouse renal
tubulointerstitial fibroblasts with basic FGF (FGF2; 134920) caused
upregulation of Kca3.1 mRNA and protein, but not of other Kca channels,
and stimulated cell proliferation. Inhibitor studies revealed that both
Kca3.1 upregulation and cell proliferation required receptor tyrosine
kinase activity and the Ras (190020)/Mek (see 176872) signaling cascade.
Pharmacologic blockade of Kca3.1 inhibited fibroblast proliferation by
G0/G1 arrest. Renal fibrosis induced by unilateral ureteral obstruction
in mice was paralleled by robust upregulation of Kca3.1 in affected
kidneys. Selective pharmacologic blockade of Kca3.1 attenuated
progression of obstruction-induced renal fibrosis.
MAPPING
By fluorescence in situ hybridization, Ghanshani et al. (1998) mapped
the KCNN4 gene to chromosome 19q13.2.
ANIMAL MODEL
Besides nitric oxide (NO) and prostacyclin, a third factor or signaling
pathway of unknown molecular identity, termed endothelium-derived
hyperpolarizing factor (EDHF), is thought to contribute to
endothelium-dependent vasodilation. Brahler et al. (2009) found that
mice with genetic Ik1 knockout combined with conditional Sk3 (KCNN3;
602983) knockout were viable, fertile, and had no overt behavioral or
neurologic defects. However, combined Ik1/Sk3 deficiency abolished
endothelial calcium-activated potassium currents and impaired
acetylcholine-induced smooth muscle hyperpolarization and EDHF-type
dilation of conduit arteries and resistance arterioles in vivo. Ik1
deficiency alone had a severe impact on acetylcholine-induced EDHF-type
vasodilation, whereas Sk3 deficiency alone impaired NO-mediated dilation
induced by acetylcholine or shear stress stimulation. Consequently,
Ik1/Sk3-deficient mice had elevated arterial blood pressure, which was
most prominent during physical activity. Overexpression of Sk3 in
double-knockout mice partially restored EDHF- and NO-type vasodilation
and lowered elevated blood pressure. Brahler et al. (2009) concluded
that SK3 and IK1 channels have distinct stimulus-dependent roles in
controlling arterial blood pressure.
Grgic et al. (2009) found that knockout of Kca3.1 protected mice from
unilateral ureteral obstruction-induced renal fibrosis,
tubulointerstitial damage, and collagen deposition, and that it
preserved renal parenchymal morphology and function.
*FIELD* RF
1. Brahler, S.; Kaistha, A.; Schmidt, V. J.; Wolfle, S. E.; Busch,
C.; Kaistha, B. P.; Kacik, M.; Hasenau, A.-L.; Grgic, I.; Si, H.;
Bond, C. T.; Adelman, J. P.; Wulff, H.; de Wit, C.; Hoyer, J.; Kohler,
R.: Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived
hyperpolarizing factor vasodilator pathway and causes hypertension. Circulation 119:
2323-2332, 2009.
2. Cheong, A.; Bingham, A. J.; Li, J.; Kumar, B.; Sukumar, P.; Munsch,
C.; Buckley, N. J.; Neylon, C. B.; Porter, K. E.; Beech, D. J.; Wood,
I. C.: Downregulated REST transcription factor is a switch enabling
critical potassium channel expression and cell proliferation. Molec.
Cell 20: 45-52, 2005.
3. Ghanshani, S.; Coleman, M.; Gustavsson, P.; Wu, A. C.-L.; Gargus,
J. J.; Gutman, G. A.; Dahl, N.; Mohrenweiser, H.; Chandy, K. G.:
Human calcium-activated potassium channel gene KCNN4 maps to chromosome
19q13.2 in the region deleted in Diamond-Blackfan anemia. Genomics 51:
160-161, 1998.
4. Grgic, I.; Kiss, E.; Kaistha, B. P.; Busch, C.; Kloss, M.; Sautter,
J.; Muller, A.; Kaistha, A.; Schmidt, C.; Raman, G.; Wulff, H.; Strutz,
F.; Grone, H.-J.; Kohler, R.; Hoyer, J.: Renal fibrosis is attenuated
by targeted disruption of K(Ca)3.1 potassium channels. Proc. Nat.
Acad. Sci. 106: 14518-14523, 2009.
5. Hoffman, J. F.; Joiner, W.; Nehrke, K.; Potapova, O.; Foye, K.;
Wickrema, A.: The hSK4 (KCNN4) isoform is the Ca(2+)-activated K(+)
channel (Gardos channel) in human red blood cells. Proc. Nat. Acad.
Sci. 100: 7366-7371, 2003.
6. Ishii, T. M.; Silvia, C.; Hirschberg, B.; Bond, C. T.; Adelman,
J. P.; Maylie, J.: A human intermediate conductance calcium-activated
potassium channel. Proc. Nat. Acad. Sci. 94: 11651-11656, 1997.
7. Joiner, W. J.; Wang, L.-Y.; Tang, M. D.; Kaczmarek, L. K.: hSK4,
a member of a novel subfamily of calcium-activated potassium channels. Proc.
Nat. Acad. Sci. 94: 11013-11018, 1997.
8. Logsdon, N. J.; Kang, J.; Togo, J. A.; Christian, E. P.; Aiyar,
J.: A novel gene, hKCa4, encodes the calcium-activated potassium
channel in human T lymphocytes. J. Biol. Chem. 272: 32723-32726,
1997.
9. Srivastava, S.; Li, Z.; Ko, K.; Choudhury, P.; Albaqumi, M.; Johnson,
A. K.; Yan, Y.; Backer, J. M.; Unutmaz, D.; Coetzee, W. A.; Skolnik,
E. Y.: Histidine phosphorylation of the potassium channel KCa3.1
by nucleoside diphosphate kinase B is required for activation of KCa3.1
and CD4 T cells. Molec. Cell 24: 665-675, 2006.
10. Toyama, K.; Wulff, H.; Chandy, K. G.; Azam, P.; Raman, G.; Saito,
T.; Fujiwara, Y.; Mattson, D. L.; Das, S.; Melvin, J. E.; Pratt, P.
F.; Hatoum, O. A.; Gutterman, D. D.; Harder, D. R.; Miura, H.: The
intermediate-conductance calcium-activated potassium channel KCa3.1
contributes to atherogenesis in mice and humans. J. Clin. Invest. 118:
3025-3037, 2008.
*FIELD* CN
Patricia A. Hartz - updated: 10/25/2011
Patricia A. Hartz - updated: 10/8/2010
Patricia A. Hartz - updated: 11/6/2008
Paul J. Converse - updated: 1/24/2007
Patricia A. Hartz - updated: 12/12/2005
Victor A. McKusick - updated: 7/14/2003
Carol A. Bocchini - updated: 4/4/1999
*FIELD* CD
Rebekah S. Rasooly: 6/24/1998
*FIELD* ED
mgross: 11/13/2011
terry: 10/25/2011
mgross: 10/8/2010
mgross: 11/17/2008
terry: 11/6/2008
alopez: 1/24/2007
mgross: 12/19/2005
wwang: 12/12/2005
tkritzer: 7/23/2003
terry: 7/14/2003
carol: 6/1/1999
mgross: 4/6/1999
carol: 4/4/1999
terry: 8/19/1998
alopez: 6/24/1998
*RECORD*
*FIELD* NO
602754
*FIELD* TI
*602754 POTASSIUM CHANNEL, CALCIUM-ACTIVATED, INTERMEDIATE/SMALL CONDUCTANCE,
SUBFAMILY N, MEMBER 4; KCNN4
read more;;IK1;;
SK4;;
KCA4;;
KCA3.1
*FIELD* TX
DESCRIPTION
The calcium-activated potassium channels (KCa channels) have been
classified into 3 groups. Large conductance (BK) channels are gated by
the concerted actions of internal calcium ions and membrane potential
and have a unit conductance of 100 to 220 picoSiemens (pS). Intermediate
conductance (IK) and small conductance (SK) channels are gated solely by
internal calcium ions, with a unit conductance of 20 to 85 pS and 2 to
20 pS, respectively, and are more sensitive to calcium than are BK
channels. Each type of channel shows a distinct pharmacology. KCNN4
belongs to a family of IK and SK channels (Ishii et al., 1997).
CLONING
Joiner et al. (1997) cloned cDNAs encoding KCNN4, which they called SK4.
The predicted 427-amino acid sequence of KCNN4 was approximately 40%
identical to that of the rat and human SK channel proteins rSK1, rSK2,
rSK3 and hSK1. Sequence analysis revealed that, like the SK channel
proteins, KCNN4 contained 6 putative transmembrane domains, a conserved
pore region, and a leucine zipper-like motif near the C terminus. By
Northern analysis, the authors found that KCNN4 was expressed as 2.6-kb
and 3.8-kb transcripts in placenta and at lower levels in lung and
pancreas. Joiner et al. (1997) proposed that KCNN4 belongs to a novel
subfamily of SK channels.
Ishii et al. (1997) also identified a cDNA encoding KCNN4, called IK1 by
them. They classified KCNN4 as an IK channel based on its physiologic
properties.
Independently, Logsdon et al. (1997) isolated a human lymph node cDNA
encoding KCNN4, which they called KCa4. Northern analysis revealed that
KCNN4 was expressed predominantly as a 2.2-kb mRNA in a variety of
tissues, with minor larger transcripts in some tissues. Logsdon et al.
(1997) found that the 2.2-kb KCNN4 transcript was 10-fold more abundant
in activated T cells than in resting T cells, concomitant with an
increase in the KCa channel current.
GENE FUNCTION
Joiner et al. (1997) found that KCNN4 generated a conductance of
approximately 12 pS and had a very high affinity for calcium when
expressed in Chinese hamster ovary cells. They concluded that KCNN4 is a
novel SK channel.
Ishii et al. (1997) classified KCNN4 as an IK channel because its
expression in Xenopus oocytes produced potassium channels with a
conductance level of 39 pS that showed the biophysical and pharmacologic
properties of native IK channels.
Logsdon et al. (1997) found that expression of KCNN4 in mammalian cells
produced channels having a conductance of 33 pS, with electrophysiologic
properties that were very similar to those reported for the native KCa
channel in activated human T lymphocytes. Logsdon et al. (1997)
suggested that KCNN4 encodes the predominant KCa channel in T
lymphocytes.
Hoffman et al. (2003) presented evidence that KCNN4 is the gene that
codes for the Ca(2+)-activated K(+) channel (Gardos channel) in red
blood cells. This channel is important pathophysiologically, because it
represents the major pathway for cell shrinkage via KCl and water loss
that occurs in sickle cell disease (603903).
Cheong et al. (2005) identified a functional REST (600571)-binding
sequence in the promoter region of the KCNN4 gene. REST was expressed in
the nuclei of human vascular smooth muscle cells (SMCs), and it
downregulated KCNN4 expression in mouse and human vascular SMCs.
Downregulated REST and upregulated KCNN4 were evident in SMCs of human
neointimal hyperplasia grown in organ culture, and exogenous REST
reduced the functional impact of KCNN4. Cheong et al. (2005) concluded
that REST acts as a switch to regulate potassium channel expression and
consequently the phenotype of vascular smooth muscle cells and human
vascular disease.
Srivastava et al. (2006) demonstrated that the 14 C-terminal amino acids
of KCa3.1 that mediate the regulation of KCa3.1 by phosphatidylinositol
3-phosphate (PI(3)P) recruit NDPKB (156491) to KCa3.1. NDPKB then
activates KCa3.1 by phosphorylating residue H358, which is present in
the same C-terminal 14-amino acid region. SiRNA treatment of NDPBK in
CD4+ T cells resulted in a marked reduction of KCa3.1 channel activity.
Srivastava et al. (2006) concluded that histidine phosphorylation
regulates KCa3.1 channel activity and that NDPBK is critical to the
channel activity and the activation of CD4 T cells.
Toyama et al. (2008) found that coronary vessels from patients with
coronary artery disease expressed elevated levels of KCa3.1.
Pharmacologic blockade and gene silencing of KCa3.1 in human vascular
smooth muscle cells (VSMCs) suppressed proliferation, migration, and
oxidative stress. In Apoe (107741) -/- mice, a genetic model of
atherosclerosis, KCa3.1 expression was elevated in VSMCs, macrophages,
and T lymphocytes that infiltrated atherosclerotic lesions, whereas VSMC
proliferation and macrophage activation was reduced. Long-term KCa3.1
blockade reduced the development of atherosclerosis in aortas of Apoe
-/- mice by suppressing VSMC proliferation and migration into plaques,
decreasing infiltration of plaques by macrophages and T lymphocytes, and
reducing oxidative stress.
Grgic et al. (2009) found that stimulation of mouse renal
tubulointerstitial fibroblasts with basic FGF (FGF2; 134920) caused
upregulation of Kca3.1 mRNA and protein, but not of other Kca channels,
and stimulated cell proliferation. Inhibitor studies revealed that both
Kca3.1 upregulation and cell proliferation required receptor tyrosine
kinase activity and the Ras (190020)/Mek (see 176872) signaling cascade.
Pharmacologic blockade of Kca3.1 inhibited fibroblast proliferation by
G0/G1 arrest. Renal fibrosis induced by unilateral ureteral obstruction
in mice was paralleled by robust upregulation of Kca3.1 in affected
kidneys. Selective pharmacologic blockade of Kca3.1 attenuated
progression of obstruction-induced renal fibrosis.
MAPPING
By fluorescence in situ hybridization, Ghanshani et al. (1998) mapped
the KCNN4 gene to chromosome 19q13.2.
ANIMAL MODEL
Besides nitric oxide (NO) and prostacyclin, a third factor or signaling
pathway of unknown molecular identity, termed endothelium-derived
hyperpolarizing factor (EDHF), is thought to contribute to
endothelium-dependent vasodilation. Brahler et al. (2009) found that
mice with genetic Ik1 knockout combined with conditional Sk3 (KCNN3;
602983) knockout were viable, fertile, and had no overt behavioral or
neurologic defects. However, combined Ik1/Sk3 deficiency abolished
endothelial calcium-activated potassium currents and impaired
acetylcholine-induced smooth muscle hyperpolarization and EDHF-type
dilation of conduit arteries and resistance arterioles in vivo. Ik1
deficiency alone had a severe impact on acetylcholine-induced EDHF-type
vasodilation, whereas Sk3 deficiency alone impaired NO-mediated dilation
induced by acetylcholine or shear stress stimulation. Consequently,
Ik1/Sk3-deficient mice had elevated arterial blood pressure, which was
most prominent during physical activity. Overexpression of Sk3 in
double-knockout mice partially restored EDHF- and NO-type vasodilation
and lowered elevated blood pressure. Brahler et al. (2009) concluded
that SK3 and IK1 channels have distinct stimulus-dependent roles in
controlling arterial blood pressure.
Grgic et al. (2009) found that knockout of Kca3.1 protected mice from
unilateral ureteral obstruction-induced renal fibrosis,
tubulointerstitial damage, and collagen deposition, and that it
preserved renal parenchymal morphology and function.
*FIELD* RF
1. Brahler, S.; Kaistha, A.; Schmidt, V. J.; Wolfle, S. E.; Busch,
C.; Kaistha, B. P.; Kacik, M.; Hasenau, A.-L.; Grgic, I.; Si, H.;
Bond, C. T.; Adelman, J. P.; Wulff, H.; de Wit, C.; Hoyer, J.; Kohler,
R.: Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived
hyperpolarizing factor vasodilator pathway and causes hypertension. Circulation 119:
2323-2332, 2009.
2. Cheong, A.; Bingham, A. J.; Li, J.; Kumar, B.; Sukumar, P.; Munsch,
C.; Buckley, N. J.; Neylon, C. B.; Porter, K. E.; Beech, D. J.; Wood,
I. C.: Downregulated REST transcription factor is a switch enabling
critical potassium channel expression and cell proliferation. Molec.
Cell 20: 45-52, 2005.
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*FIELD* CN
Patricia A. Hartz - updated: 10/25/2011
Patricia A. Hartz - updated: 10/8/2010
Patricia A. Hartz - updated: 11/6/2008
Paul J. Converse - updated: 1/24/2007
Patricia A. Hartz - updated: 12/12/2005
Victor A. McKusick - updated: 7/14/2003
Carol A. Bocchini - updated: 4/4/1999
*FIELD* CD
Rebekah S. Rasooly: 6/24/1998
*FIELD* ED
mgross: 11/13/2011
terry: 10/25/2011
mgross: 10/8/2010
mgross: 11/17/2008
terry: 11/6/2008
alopez: 1/24/2007
mgross: 12/19/2005
wwang: 12/12/2005
tkritzer: 7/23/2003
terry: 7/14/2003
carol: 6/1/1999
mgross: 4/6/1999
carol: 4/4/1999
terry: 8/19/1998
alopez: 6/24/1998