ID   PDE9A_MOUSE             Reviewed;         534 AA.
AC   O70628;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1998, sequence version 1.
DT   27-MAR-2024, entry version 170.
DE   RecName: Full=High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305};
DE            EC=3.1.4.35 {ECO:0000269|PubMed:9624145};
GN   Name=Pde9a; Synonyms=Pde8b;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, ACTIVITY
RP   REGULATION, AND TISSUE SPECIFICITY.
RX   PubMed=9624145; DOI=10.1074/jbc.273.25.15553;
RA   Soderling S.H., Bayuga S.J., Beavo J.A.;
RT   "Identification and characterization of a novel family of cyclic nucleotide
RT   phosphodiesterases.";
RL   J. Biol. Chem. 273:15553-15558(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=9856478; DOI=10.1007/s004390050838;
RA   Guipponi M., Scott H.S., Kudoh J., Kawasaki K., Shibuya K., Shintani A.,
RA   Asakawa S., Chen H., Lalioti M.D., Rossier C., Minoshima S., Shimizu N.,
RA   Antonarakis S.E.;
RT   "Identification and characterization of a novel cyclic nucleotide
RT   phosphodiesterase gene (PDE9A) that maps to 21q22.3: alternative splicing
RT   of mRNA transcripts, genomic structure and sequence.";
RL   Hum. Genet. 103:386-392(1998).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
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   [4]
RP   TISSUE SPECIFICITY.
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   [5]
RP   FUNCTION, AND ACTIVITY REGULATION.
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).
RN   [6]
RP   FUNCTION.
RX   PubMed=24746365; DOI=10.1016/j.neurobiolaging.2014.03.023;
RA   Kroker K.S., Mathis C., Marti A., Cassel J.C., Rosenbrock H.,
RA   Dorner-Ciossek C.;
RT   "PDE9A inhibition rescues amyloid beta-induced deficits in synaptic
RT   plasticity and cognition.";
RL   Neurobiol. Aging 35:2072-2078(2014).
RN   [7]
RP   FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX   PubMed=25799991; DOI=10.1038/nature14332;
RA   Lee D.I., Zhu G., Sasaki T., Cho G.S., Hamdani N., Holewinski R., Jo S.H.,
RA   Danner T., Zhang M., Rainer P.P., Bedja D., Kirk J.A., Ranek M.J.,
RA   Dostmann W.R., Kwon C., Margulies K.B., Van Eyk J.E., Paulus W.J.,
RA   Takimoto E., Kass D.A.;
RT   "Phosphodiesterase 9A controls nitric-oxide-independent cGMP and
RT   hypertrophic heart disease.";
RL   Nature 519:472-476(2015).
CC   -!- FUNCTION: Specifically hydrolyzes the second messenger cGMP, which is a
CC       key regulator of many important physiological processes
CC       (PubMed:9624145). Highly specific: compared to other members of the
CC       cyclic nucleotide phosphodiesterase family, has the highest affinity
CC       and selectivity for cGMP. Specifically regulates natriuretic-peptide-
CC       dependent cGMP signaling in heart, acting as a regulator of cardiac
CC       hypertrophy in myocytes and muscle. Does not regulate nitric oxide-
CC       dependent cGMP in heart (PubMed:25799991). Additional experiments are
CC       required to confirm whether its ability to hydrolyze natriuretic-
CC       peptide-dependent cGMP is specific to heart or is a general feature of
CC       the protein (Probable). In brain, involved in cognitive function, such
CC       as learning and long-term memory (PubMed:22328573, PubMed:24746365).
CC       {ECO:0000269|PubMed:22328573, ECO:0000269|PubMed:24746365,
CC       ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624145, ECO:0000305}.
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:0000269|PubMed:9624145};
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: Inhibited by SCH 51866 and moderately, by
CC       zaprinast. Specifically inhibited by PF-04447943 (6-[(3S,4S)-4-methyl-
CC       1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-
CC       1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) (PubMed:22328573).
CC       {ECO:0000269|PubMed:22328573, ECO:0000269|PubMed:9624145}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.07 mM for cGMP {ECO:0000269|PubMed:9624145};
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   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=1;
CC         Comment=A number of isoforms are produced.;
CC       Name=1;
CC         IsoId=O70628-1; Sequence=Displayed;
CC   -!- TISSUE SPECIFICITY: Highly expressed in kidney. Lower levels in liver,
CC       lung and brain (PubMed:9624145). Widely expressed in brain, with
CC       highest expression in cerebellar Purkinje cells (PubMed:14501210).
CC       Present in heart (at protein level) (PubMed:25799991).
CC       {ECO:0000269|PubMed:14501210, ECO:0000269|PubMed:25799991,
CC       ECO:0000269|PubMed:9624145}.
CC   -!- DISRUPTION PHENOTYPE: Mice hearts develop less dilation and dysfunction
CC       when exposed to sustained pressure overload.
CC       {ECO:0000269|PubMed:25799991}.
CC   -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC       PDE9 subfamily. {ECO:0000305}.
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DR   EMBL; AF031147; AAC24344.1; -; mRNA.
DR   EMBL; AF068247; AAC23996.1; -; mRNA.
DR   EMBL; BC061163; AAH61163.1; -; mRNA.
DR   CCDS; CCDS28605.1; -. [O70628-1]
DR   RefSeq; NP_001157220.1; NM_001163748.1. [O70628-1]
DR   RefSeq; NP_032830.3; NM_008804.4. [O70628-1]
DR   AlphaFoldDB; O70628; -.
DR   SMR; O70628; -.
DR   BioGRID; 202083; 1.
DR   STRING; 10090.ENSMUSP00000038005; -.
DR   BindingDB; O70628; -.
DR   ChEMBL; CHEMBL5169102; -.
DR   iPTMnet; O70628; -.
DR   PhosphoSitePlus; O70628; -.
DR   MaxQB; O70628; -.
DR   PaxDb; 10090-ENSMUSP00000038005; -.
DR   ProteomicsDB; 287991; -. [O70628-1]
DR   Antibodypedia; 1648; 263 antibodies from 33 providers.
DR   DNASU; 18585; -.
DR   Ensembl; ENSMUST00000047168.13; ENSMUSP00000038005.6; ENSMUSG00000041119.13. [O70628-1]
DR   Ensembl; ENSMUST00000127929.8; ENSMUSP00000117611.2; ENSMUSG00000041119.13. [O70628-1]
DR   GeneID; 18585; -.
DR   KEGG; mmu:18585; -.
DR   UCSC; uc008buz.2; mouse. [O70628-1]
DR   AGR; MGI:1277179; -.
DR   CTD; 5152; -.
DR   MGI; MGI:1277179; Pde9a.
DR   VEuPathDB; HostDB:ENSMUSG00000041119; -.
DR   eggNOG; KOG3689; Eukaryota.
DR   GeneTree; ENSGT00940000155587; -.
DR   InParanoid; O70628; -.
DR   OMA; HPGFNNY; -.
DR   OrthoDB; 5479253at2759; -.
DR   PhylomeDB; O70628; -.
DR   TreeFam; TF314638; -.
DR   BRENDA; 3.1.4.35; 3474.
DR   Reactome; R-MMU-418457; cGMP effects.
DR   SABIO-RK; O70628; -.
DR   UniPathway; UPA00763; UER00748.
DR   BioGRID-ORCS; 18585; 1 hit in 78 CRISPR screens.
DR   ChiTaRS; Pde9a; mouse.
DR   PRO; PR:O70628; -.
DR   Proteomes; UP000000589; Chromosome 17.
DR   RNAct; O70628; Protein.
DR   Bgee; ENSMUSG00000041119; Expressed in cortical plate and 227 other cell types or tissues.
DR   ExpressionAtlas; O70628; baseline and differential.
DR   GO; GO:0005829; C:cytosol; ISO:MGI.
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; ISO:MGI.
DR   GO; GO:0043204; C:perikaryon; ISO:MGI.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; ISO:MGI.
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:MGI.
DR   GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0046069; P:cGMP catabolic process; IDA:UniProtKB.
DR   GO; GO:0046068; P:cGMP metabolic process; ISO:MGI.
DR   GO; GO:2000178; P:negative regulation of neural precursor cell proliferation; ISO:MGI.
DR   GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; IMP:UniProtKB.
DR   GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISO:MGI.
DR   GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR   CDD; cd00077; HDc; 1.
DR   Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 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   PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1.
DR   PANTHER; PTHR11347:SF230; HIGH AFFINITY CGMP-SPECIFIC 3',5'-CYCLIC PHOSPHODIESTERASE 9A; 1.
DR   Pfam; PF00233; PDEase_I; 1.
DR   PRINTS; PR00387; PDIESTERASE1.
DR   SMART; SM00471; HDc; 1.
DR   SUPFAM; SSF109604; HD-domain/PDEase-like; 1.
DR   PROSITE; PS00126; PDEASE_I_1; 1.
DR   PROSITE; PS51845; PDEASE_I_2; 1.
DR   Genevisible; O70628; MM.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cell membrane; Cell projection; cGMP; Cytoplasm;
KW   Endoplasmic reticulum; Golgi apparatus; Hydrolase; Magnesium; Membrane;
KW   Metal-binding; Phosphoprotein; Reference proteome; Zinc.
FT   CHAIN           1..534
FT                   /note="High affinity cGMP-specific 3',5'-cyclic
FT                   phosphodiesterase 9A"
FT                   /id="PRO_0000198842"
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:0000250|UniProtKB:Q8QZV1"
SQ   SEQUENCE   534 AA;  61636 MW;  28126C7BB7375241 CRC64;
     MGAGSSSYRP KAIYLDIDGR IQKVVFSKYC NSSDIMDLFC IATGLPRNTT ISLLTTDDAM
     VSIDPTMPAN SERTPYKVRP VAVKQVSERE ELIQGVLAQV AEQFSRAFKI NELKAEVANH
     LAVLEKRVEL EGLKVVEIEK CKSDIKKMRE ELAARNSRTN CPCKYSFLDN KKLTPRRDVP
     TYPKYLLSPE TIEALRKPTF DVWLWEPNEM LSCLEHMYHD LGLVRDFSIN PITLRRWLLC
     VHDNYRNNPF HNFRHCFCVT QMMYSMVWLC GLQEKFSQMD ILVLMTAAIC HDLDHPGYNN
     TYQINARTEL AVRYNDISPL ENHHCAIAFQ ILARPECNIF ASVPPEGFRQ IRQGMITLIL
     ATDMARHAEI MDSFKEKMEN FDYSNEEHLT LLKMILIKCC DISNEVRPME VAEPWVDCLL
     EEYFMQSDRE KSEGLPVAPF MDRDKVTKAT AQIGFIKFVL IPMFETVTKL FPVVEETMLR
     PLWESREHYE ELKQLDDAMK ELQKKTESLT SGAPENTTEK NRDAKDSEGH SPPN
//