PDE9A_RAT
ID PDE9A_RAT Reviewed; 534 AA.
AC Q8QZV1; F1LRG6;
DT 27-MAY-2015, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 03-AUG-2022, entry version 132.
DE RecName: Full=High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305};
DE EC=3.1.4.35 {ECO:0000250|UniProtKB:O76083};
GN Name=Pde9a {ECO:0000312|RGD:621035};
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.
RC STRAIN=Sprague-Dawley;
RX PubMed=11698617; DOI=10.1523/jneurosci.21-22-09068.2001;
RA Andreeva S.G., Dikkes P., Epstein P.M., Rosenberg P.A.;
RT "Expression of cGMP-specific phosphodiesterase 9A mRNA in the rat brain.";
RL J. Neurosci. 21:9068-9076(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=Sprague-Dawley;
RX PubMed=14501210; DOI=10.1023/a:1025704031210;
RA van Staveren W.C., Glick J., Markerink-van Ittersum M., Shimizu M.,
RA Beavo J.A., Steinbusch H.W., de Vente J.;
RT "Cloning and localization of the cGMP-specific phosphodiesterase type 9 in
RT the rat brain.";
RL J. Neurocytol. 31:729-741(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-318, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=16641100; DOI=10.1073/pnas.0600895103;
RA Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.;
RT "Quantitative phosphoproteomics of vasopressin-sensitive renal cells:
RT regulation of aquaporin-2 phosphorylation at two sites.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006).
RN [6]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=18674549; DOI=10.1016/j.neuropharm.2008.07.005;
RA van der Staay F.J., Rutten K., Baerfacker L., Devry J., Erb C.,
RA Heckroth H., Karthaus D., Tersteegen A., van Kampen M., Blokland A.,
RA Prickaerts J., Reymann K.G., Schroeder U.H., Hendrix M.;
RT "The novel selective PDE9 inhibitor BAY 73-6691 improves learning and
RT memory in rodents.";
RL Neuropharmacology 55:908-918(2008).
RN [7]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=22070409; DOI=10.3109/01677063.2011.630494;
RA Vardigan J.D., Converso A., Hutson P.H., Uslaner J.M.;
RT "The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 attenuates
RT a scopolamine-induced deficit in a novel rodent attention task.";
RL J. Neurogenet. 25:120-126(2011).
RN [8]
RP FUNCTION.
RX PubMed=22328573; DOI=10.1124/jpet.111.191353;
RA Kleiman R.J., Chapin D.S., Christoffersen C., Freeman J., Fonseca K.R.,
RA Geoghegan K.F., Grimwood S., Guanowsky V., Hajos M., Harms J.F.,
RA Helal C.J., Hoffmann W.E., Kocan G.P., Majchrzak M.J., McGinnis D.,
RA McLean S., Menniti F.S., Nelson F., Roof R., Schmidt A.W., Seymour P.A.,
RA Stephenson D.T., Tingley F.D., Vanase-Frawley M., Verhoest P.R.,
RA Schmidt C.J.;
RT "Phosphodiesterase 9A regulates central cGMP and modulates responses to
RT cholinergic and monoaminergic perturbation in vivo.";
RL J. Pharmacol. Exp. Ther. 341:396-409(2012).
CC -!- FUNCTION: Specifically hydrolyzes the second messenger cGMP, which is a
CC key regulator of many important physiological processes. Highly
CC specific: compared to other members of the cyclic nucleotide
CC phosphodiesterase family, has the highest affinity and selectivity for
CC cGMP. Specifically regulates natriuretic-peptide-dependent cGMP
CC signaling in heart, acting as a regulator of cardiac hypertrophy in
CC myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in
CC heart. Additional experiments are required to confirm whether its
CC ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to
CC heart or is a general feature of the protein (By similarity). In brain,
CC involved in cognitive function, such as learning and long-term memory
CC (PubMed:18674549, PubMed:22070409, PubMed:22328573).
CC {ECO:0000250|UniProtKB:O76083, ECO:0000269|PubMed:18674549,
CC ECO:0000269|PubMed:22070409, ECO:0000269|PubMed:22328573}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3',5'-cyclic GMP + H2O = GMP + H(+); Xref=Rhea:RHEA:16957,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57746,
CC ChEBI:CHEBI:58115; EC=3.1.4.35;
CC Evidence={ECO:0000250|UniProtKB:O76083};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:O76083};
CC Note=Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per
CC subunit: site 1 preferentially binds zinc, while site 2 has a
CC preference for magnesium. Tightly binds zinc.
CC {ECO:0000250|UniProtKB:O76083};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:O76083};
CC Note=Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations
CC per subunit: site 1 preferentially binds zinc, while site 2 has a
CC preference for magnesium. Binds magnesium less tightly than zinc.
CC {ECO:0000250|UniProtKB:O76083};
CC -!- ACTIVITY REGULATION: Specifically inhibited by BAY-73-6691 (1-(2-
CC chlorophenyl)-6-((2R)-3,3,3- trifluoro-2-methylpropyl)-1,5-dihydro-4H-
CC pyrazolo(3,4-d)pyrimidine-4-one) (PubMed:18674549). Specifically
CC inhibited by PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-
CC ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-
CC pyrazolo[3,4-d]pyrimidin-4-one) (PubMed:22070409).
CC {ECO:0000269|PubMed:18674549, ECO:0000269|PubMed:22070409}.
CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from
CC 3',5'-cyclic GMP: step 1/1.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:O76083}.
CC -!- SUBCELLULAR LOCATION: Cell projection, ruffle membrane
CC {ECO:0000250|UniProtKB:O76083}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:O76083}. Golgi apparatus
CC {ECO:0000250|UniProtKB:O76083}. Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:O76083}. Cell membrane, sarcolemma
CC {ECO:0000250|UniProtKB:O76083}.
CC -!- TISSUE SPECIFICITY: Widely expressed in brain: highly expressed in the
CC basal forebrain, cerebellum and olfactory bulb (PubMed:11698617,
CC PubMed:14501210). Expressed at highest level in cerebellar Purkinje
CC cells (PubMed:14501210). {ECO:0000269|PubMed:11698617,
CC ECO:0000269|PubMed:14501210}.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC PDE9 subfamily. {ECO:0000305}.
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DR EMBL; AF372654; AAL99404.1; -; mRNA.
DR EMBL; AY145898; AAN64274.1; -; mRNA.
DR EMBL; AABR06100132; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06100133; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06100134; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR06100135; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC161837; AAI61837.1; -; mRNA.
DR RefSeq; NP_612552.1; NM_138543.1.
DR RefSeq; XP_008771015.1; XM_008772793.2.
DR RefSeq; XP_008771016.1; XM_008772794.2.
DR RefSeq; XP_008771017.1; XM_008772795.2.
DR AlphaFoldDB; Q8QZV1; -.
DR SMR; Q8QZV1; -.
DR STRING; 10116.ENSRNOP00000001559; -.
DR BindingDB; Q8QZV1; -.
DR ChEMBL; CHEMBL3638358; -.
DR iPTMnet; Q8QZV1; -.
DR PhosphoSitePlus; Q8QZV1; -.
DR PaxDb; Q8QZV1; -.
DR Ensembl; ENSRNOT00000001559; ENSRNOP00000001559; ENSRNOG00000001174.
DR GeneID; 191569; -.
DR KEGG; rno:191569; -.
DR UCSC; RGD:621035; rat.
DR CTD; 5152; -.
DR RGD; 621035; Pde9a.
DR eggNOG; KOG3689; Eukaryota.
DR GeneTree; ENSGT00940000155587; -.
DR HOGENOM; CLU_032104_1_0_1; -.
DR OMA; ECNIFCH; -.
DR OrthoDB; 904682at2759; -.
DR PhylomeDB; Q8QZV1; -.
DR TreeFam; TF314638; -.
DR BRENDA; 3.1.4.35; 5301.
DR Reactome; R-RNO-418457; cGMP effects.
DR UniPathway; UPA00763; UER00748.
DR PRO; PR:Q8QZV1; -.
DR Proteomes; UP000002494; Chromosome 20.
DR Bgee; ENSRNOG00000001174; Expressed in jejunum and 18 other tissues.
DR Genevisible; Q8QZV1; RN.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0043204; C:perikaryon; IDA:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0042383; C:sarcolemma; ISS:UniProtKB.
DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IDA:RGD.
DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046069; P:cGMP catabolic process; ISS:UniProtKB.
DR GO; GO:0046068; P:cGMP metabolic process; ISS:UniProtKB.
DR GO; GO:0019934; P:cGMP-mediated signaling; IEP:RGD.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; ISS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00077; HDc; 1.
DR Gene3D; 1.10.1300.10; -; 1.
DR InterPro; IPR003607; HD/PDEase_dom.
DR InterPro; IPR023088; PDEase.
DR InterPro; IPR002073; PDEase_catalytic_dom.
DR InterPro; IPR036971; PDEase_catalytic_dom_sf.
DR InterPro; IPR023174; PDEase_CS.
DR Pfam; PF00233; PDEase_I; 1.
DR PRINTS; PR00387; PDIESTERASE1.
DR SMART; SM00471; HDc; 1.
DR PROSITE; PS00126; PDEASE_I_1; 1.
DR PROSITE; PS51845; PDEASE_I_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; cGMP; Cytoplasm; Endoplasmic reticulum;
KW Golgi apparatus; Hydrolase; Magnesium; Membrane; Metal-binding;
KW Phosphoprotein; Reference proteome; Zinc.
FT CHAIN 1..534
FT /note="High affinity cGMP-specific 3',5'-cyclic
FT phosphodiesterase 9A"
FT /id="PRO_0000433157"
FT DOMAIN 175..496
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 500..534
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 518..534
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 251
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 251..255
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 255
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 291
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 292
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 292
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 292
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 401
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 401
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 423
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 451..452
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT MOD_RES 318
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16641100"
SQ SEQUENCE 534 AA; 61756 MW; 4AB9382BA2D2CB54 CRC64;
MGAGSSSYRP KAIYLDIDGR IQKVVFSKYC NSSDIMDLFC IATGLPRNTT ISLLTTDDAM
VSIDPTMPAN SERTPYKVRP VAVKQVSERE ELVQGVLAQV AEQFSRAFKI NELKAEVANH
LAMLEKRVEL EGLKVVEIEK CKSDIKKMRE ELAARNNRTN CPCKYSFLDN KKLTPRRDVP
TYPKYLLSPE TIEALRKPTF DVWLWEPNEM LSCLEHMYHD LGLVRDFSIN PITLRRWLLC
VHDNYRSNPF HNFRHCFCVT QMMYSMVWLC GLQEKFSQMD ILVLMTAAIC HDLDHPGYNN
TYQINARTEL AVRYNDISPL ENHHCAIAFQ ILARPECNIF ASVPPEGFRQ IRQGMITLIL
ATDMARHAEI MDSFKEKMEN FDYSNEEHLT LLKMILIKCC DISNEVRPME VAEPWVDCLL
EEYFMQSDRE KSEGLPVAPF MDRDKVTKAT AQIGFIKFVL IPMFETVTKL FPIVEETMLR
PLWESREHYE ELKQLDDAMK ELQKKTENLT SGATENAPEK TRDAKDNEDR SPPN
