Affinage

PDE3A

cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A · UniProt Q14432

Length
1141 aa
Mass
125.0 kDa
Annotated
2026-06-10
71 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDE3A is a cGMP-inhibited, cAMP-hydrolyzing phosphodiesterase that sets local cyclic-nucleotide tone within signalosomes controlling smooth muscle proliferation, cardiac contractility, oocyte meiosis, and—when pharmacologically subverted—cancer cell death (PMID:25593322, PMID:25961942, PMID:21632535). The enzyme is expressed as multiple isoforms (PDE3A1/PDE3A2/PDE3A-94 and related forms) generated pre-translationally from a single gene; their differing N-termini contain membrane-association domains that determine soluble versus particulate localization, with N-terminal truncation shifting the enzyme to the cytosol (PMID:12154085, PMID:11420239, PMID:11115397). Catalysis depends on a metal-binding active site in residues ~679–1141 in which conserved histidines and glutamates (H752, H756, H840, E825) are required for turnover while residues such as E866/H836/H869 govern cAMP and cGMP binding at overlapping but non-identical sites (PMID:10828019, PMID:8695850, PMID:9826434); the enzyme hydrolyzes cAMP with high affinity and can also turn over cUMP as a low-affinity substrate (PMID:27975297). PDE3A activity, localization, and partner binding are tuned by phosphorylation: PKA, PKC, and PKB/Akt phosphorylate distinct serines in an isoform-selective manner, creating 14-3-3 binding sites and controlling incorporation into a sarcoplasmic-reticulum SERCA2/AKAP18/phospholamban signalosome where PKA phosphorylation of the PDE3A1-unique Ser-292/293 promotes SERCA2 association and modulates SERCA2 activity (PMID:17124499, PMID:25593322, PMID:19261611, PMID:24248367). Through compartmentalized cAMP, PDE3A restrains the PKA→Raf-1/ERK and PKA/CREB→p21 axes to permit vascular smooth muscle proliferation, and dominant gain-of-function missense mutations that increase PKA-mediated phosphorylation and cAMP hydrolysis cause autosomal-dominant hypertension with brachydactyly by enhancing VSMC and chondrocyte proliferation (PMID:25961942, PMID:21632535). In oocytes, PKB/Akt phosphorylation at Ser-290–292 activates PDE3A to lower cAMP and drive meiotic resumption, coupling to Plk1/Cdc2 control (PMID:17124499, PMID:21099356). PDE3A is also a druggable scaffold: small-molecule 'molecular glues' such as DNMDP occupy a pocket in the PDE3A catalytic domain and create a neomorphic interface that recruits the C-terminal helix of Schlafen 12 (SLFN12) into a butterfly-shaped heterotetramer, activating SLFN12 RNase activity—dependent on SLFN12 dephosphorylation—to block translation and trigger cancer cell apoptosis (PMID:26656089, PMID:34272366, PMID:34707099, PMID:35104454).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1996 Medium

    Defining where catalysis resides was the first step toward understanding PDE3A as an enzyme; deletion mapping localized the catalytic domain to a discrete C-terminal region.

    Evidence Deletion mutagenesis expressed in PDE-deficient yeast with activity assays

    PMID:8695850

    Open questions at the time
    • Does not identify catalytic residues
    • No structural model of the active site
  2. 1998 Medium

    To explain catalysis and inhibitor selectivity, active-site residues were tested; specific histidines were shown essential for activity and metal coordination while another residue defined the inhibitory binding site, and a unique cysteine was required for folding.

    Evidence Site-directed mutagenesis in yeast with kinetic analysis of cGMP and milrinone inhibition

    PMID:9826434

    Open questions at the time
    • Roles inferred from kinetics without crystal structure
    • Metal coordination geometry not directly resolved
  3. 1998 Medium

    Establishing the cellular context, PDE3A and PDE3B were shown to occupy distinct subcellular compartments in vascular smooth muscle and to be upregulated by sustained cAMP elevation.

    Evidence Isoform-specific RT-PCR, immunoblotting, and subcellular fractionation in rat VSMCs

    PMID:9884079

    Open questions at the time
    • Mechanism of cAMP-induced upregulation unresolved
    • Functional consequence of compartmentalization not defined
  4. 2000 High

    Extending the active-site model, systematic mutagenesis showed cAMP and cGMP bind overlapping but non-identical residues, explaining how cGMP can act as a competitive inhibitor.

    Evidence Site-directed mutagenesis in Sf9 cells with kcat/Km/Ki determination under defined metal conditions

    PMID:10828019

    Open questions at the time
    • No structural visualization of the dual binding mode
    • Does not address allosteric regulation by phosphorylation
  5. 2001 Medium

    The structural basis of localization was traced to the N-terminus; truncation forms partition to cytosol while retaining catalytic kinetics, and a VSMC-specific isoform lacking the N-terminal 145 residues was shown to arise pre-translationally from the same gene.

    Evidence cDNA cloning, expression with fractionation and kinetics in oocyte and aortic myocyte systems

    PMID:11115397 PMID:11420239

    Open questions at the time
    • Membrane-targeting sequence not mapped at residue level
    • Tissue-specific isoform regulation mechanism unclear
  6. 2002 High

    Isoform architecture was systematically defined, linking distinct N-termini to membrane-association domains and to differential PKA/PKB phosphorylation site content, framing isoforms as functionally specialized.

    Evidence Isoform-specific antibodies, Western blotting, and in vitro transcription/translation in cardiac myocytes

    PMID:12154085

    Open questions at the time
    • Functional consequences of each phospho-site not yet tested
    • In vivo isoform-specific roles undefined
  7. 2002 Medium

    Reciprocal regulation by cyclic nucleotides was demonstrated in smooth muscle: PKA activates PDE3A while cGMP inhibits it, establishing PDE3A as a node integrating cAMP and cGMP signaling.

    Evidence Phosphorylation and activity assays with PKA and cGMP-synthesis modulators in gastric smooth muscle cells

    PMID:11832336

    Open questions at the time
    • Phosphosite mediating PKA activation not mapped here
    • Stoichiometry of cGMP inhibition in cells not quantified
  8. 2006 High

    A physiological kinase-substrate link was established: PKB/Akt phosphorylation at Ser-290–292 activates PDE3A and is required for oocyte meiotic resumption, connecting growth-factor signaling to cyclic-nucleotide control of meiosis.

    Evidence Cell-free kinase assays, mutagenesis, and myr-Akt microinjection with pde3a(-/-) rescue across Xenopus and mouse oocytes

    PMID:17124499

    Open questions at the time
    • Does not resolve downstream cell-cycle effectors
    • Relative contribution of Akt vs PKA in vivo unquantified
  9. 2009 High

    In platelets, agonist signaling was shown to act through PKC—not PI3K/PKB—to phosphorylate multiple PDE3A serines, increasing activity and 14-3-3 binding, demonstrating pathway-selective control of the enzyme.

    Evidence Phosphoproteomic site mapping, pharmacological pathway dissection, co-IP, and activity assays in platelets

    PMID:19261611

    Open questions at the time
    • Functional role of each individual phosphosite not isolated
    • How 14-3-3 binding alters localization not shown
  10. 2010 Medium

    PDE3A was placed within a plasma-membrane microdomain controlling an ion channel, showing it physically and functionally couples to CFTR to generate compartmentalized cAMP dependent on the actin cytoskeleton.

    Evidence Co-IP, patch-clamp, actin disruption, and gland secretion model

    PMID:20089840

    Open questions at the time
    • Direct vs scaffold-mediated PDE3A–CFTR interaction unresolved
    • Adaptor anchoring PDE3A to actin not identified
  11. 2010 Medium

    The oocyte arrest phenotype was mechanistically linked downstream: loss of PDE3A elevates PKA, which inactivates Plk1 and Cdc2, and PDE3A co-localizes with Plk1, defining the cell-cycle machinery controlled by PDE3A-regulated cAMP.

    Evidence PDE3A(-/-) oocytes, co-IP, co-localization, in vitro Plk1 phosphorylation, and PKA-inhibitor rescue

    PMID:21099356

    Open questions at the time
    • Whether PDE3A–Plk1 interaction is direct unproven
    • Physiological role of the interaction beyond meiosis unclear
  12. 2011 High

    The proliferative role of PDE3A in vasculature was mechanistically dissected: deleting PDE3A engages two PKA-dependent brakes (Raf-1/ERK inhibition and CREB/p21/p53 induction) to arrest the cell cycle, explaining how PDE3A-controlled cAMP permits VSMC growth.

    Evidence PDE3A-KO VSMCs with proliferation assays, pathway analysis, CREB constructs, and p53 siRNA

    PMID:21632535

    Open questions at the time
    • Spatial pool of cAMP driving each branch not localized
    • Relative weight of the two pathways in vivo unquantified
  13. 2013 High

    Isoform-selective regulation was demonstrated functionally: PKA and PKC phosphorylate distinct sites on PDE3A1 (S312) versus PDE3A2 (S428), with differential activity effects and distinct interactomes, establishing the isoforms as separately wired signaling units.

    Evidence Tagged isoform expression, gel filtration, 2D electrophoresis co-IP, and phospho-specific activity assays in HEK293 and myocardium

    PMID:24248367

    Open questions at the time
    • Identities of isoform-specific interactors largely unresolved
    • In vivo relevance of S312 14-3-3 binding for PDE3A1 unclear
  14. 2015 High

    PDE3A was shown to nucleate a cardiac SR signalosome with SERCA2, phospholamban, and AKAP18, with PKA phosphorylation of the PDE3A1-unique Ser-292/293 controlling SERCA2 association and activity, providing a structural basis for local cAMP control of calcium handling.

    Evidence Co-IP, gel filtration, PKA phosphorylation, mutagenesis, N-terminal deletions, and SERCA2 activity assays

    PMID:25593322

    Open questions at the time
    • Stoichiometry and architecture of the signalosome unresolved
    • Direct vs AKAP-bridged SERCA2 contact not distinguished
  15. 2015 High

    A direct disease link was established: gain-of-function PDE3A mutations cause autosomal-dominant hypertension with brachydactyly by increasing PKA-mediated phosphorylation and cAMP hydrolysis, driving VSMC and chondrocyte proliferation.

    Evidence Mutation analysis across six families with functional assays in mesenchymal-derived VSMCs and chondrocytes

    PMID:25961942

    Open questions at the time
    • How mutations increase PKA accessibility structurally unknown
    • Link between VASP/PTHrP dysregulation and brachydactyly incomplete
  16. 2015 High

    A neomorphic pharmacology was discovered: DNMDP binding to PDE3A creates a gain-of-function interaction with SLFN12, with co-expression of both proteins required for cancer-cell sensitivity, reframing PDE3A as a molecular-glue scaffold for cytotoxicity.

    Evidence Phenotypic screening across 766 cell lines, chemogenomic deconvolution, and PDE3A/SLFN12 depletion

    PMID:26656089

    Open questions at the time
    • Mechanism of SLFN12 activation not yet defined here
    • Structure of the induced complex not yet resolved
  17. 2015 Medium

    Chemical proteomics confirmed endogenous PDE3A partners, identifying 14-3-3 proteins and a PP2A holoenzyme as associated with PDE3A, expanding its regulatory interactome.

    Evidence IBMX-resin affinity capture with competitor selectivity and mass spectrometry in HeLa lysates

    PMID:26205238

    Open questions at the time
    • Functional consequence of PP2A association not tested
    • Direct vs indirect binding not distinguished
  18. 2016 Medium

    The substrate scope was broadened: PDE3A hydrolyzes cUMP as a low-affinity, high-velocity substrate sensitive to milrinone, indicating PDE3A activity is not restricted to cAMP/cGMP.

    Evidence Enzyme kinetics with HPLC-MS/MS product detection and milrinone inhibition

    PMID:27975297

    Open questions at the time
    • Physiological relevance of cUMP hydrolysis unknown
    • Cellular cUMP levels not measured
  19. 2017 Medium

    Transcriptional control of PDE3A was addressed: SFPQ acts as a transcriptional activator binding upstream regulatory regions to modulate serum-induced PDE3A mRNA, identifying a determinant of PDE3A expression levels.

    Evidence 5'-RACE TSS mapping, ChIP-seq, and SFPQ overexpression/knockdown with mRNA measurement

    PMID:28743736

    Open questions at the time
    • Whether SFPQ regulation is isoform-selective unclear
    • Signal coupling serum to SFPQ binding unresolved
  20. 2019 Medium

    Promoter-level regulation in heart was defined: ATF3 binds a promoter insertion to repress cAMP-dependent PDE3A transcription, linking a common indel genotype to PDE3A expression and PDE3-inhibitor response in failing hearts.

    Evidence Luciferase reporter assays, ATF3 binding analysis, and RT-PCR/activity in explanted failing left ventricles

    PMID:30871701

    Open questions at the time
    • Direct ATF3 occupancy in vivo not shown
    • Clinical impact of genotype on therapy not established
  21. 2020 Medium

    PDE3A was positioned as an intermediary in vascular NO signaling: NO via sGC/cGMP raises PDE3A expression and activity to lower cAMP and activate AMPK, with PDE3A knockdown blunting AMPK activation.

    Evidence siRNA knockdown in hPASMC with cAMP measurement, sGC pharmacology, and AMPK phospho-blotting

    PMID:32914566

    Open questions at the time
    • Apparent contrast with direct cGMP inhibition of PDE3A not reconciled
    • Mechanism of NO-induced PDE3A upregulation unknown
  22. 2021 High

    The structural mechanism of the molecular-glue effect was solved: cryo-EM of PDE3A–SLFN12 heterotetramers showed compounds packed in a PDE3A catalytic-domain pocket creating an interface that captures the SLFN12 C-terminal helix and activates SLFN12 RNase activity essential for cytotoxicity.

    Evidence Cryo-EM structures with anagrelide/nauclefine/DNMDP, interface mutagenesis, RNase and viability assays, and xenografts

    PMID:34272366 PMID:34707099

    Open questions at the time
    • RNA substrate specificity of activated SLFN12 not fully mapped
    • Why only certain cells are sensitive beyond SLFN12 expression unclear
  23. 2022 High

    The activation switch downstream of complex formation was identified: glue-induced PDE3A binding stabilizes SLFN12 and drives its dephosphorylation at Ser-368/Ser-573, which is required to unleash its rRNA RNase activity and cell death.

    Evidence SLFN12 phosphosite mutagenesis, co-IP, stability, RNase, and cell-death assays

    PMID:35104454

    Open questions at the time
    • Phosphatase responsible for SLFN12 dephosphorylation unidentified
    • How PDE3A binding triggers dephosphorylation unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers—isoform-specific phosphorylation, signalosome assembly, transcriptional control, and cGMP inhibition—are integrated to shape spatially distinct cAMP pools in a given cell type remains undefined, as does the endogenous physiological role (if any) of the PDE3A–SLFN12 axis.
  • No full-length multi-isoform structure with phosphorylation states
  • Endogenous trigger for PDE3A–SLFN12 interaction unknown
  • Integrated quantitative model of compartmentalized cAMP lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 2 GO:0098772 molecular function regulator activity 2 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 1
Partners
AKAP18CFTRPHOSPHOLAMBANPLK1PPP2 (PP2A)SERCA2SLFN12YWHA (14-3-3)
Complex memberships
PDE3A-SLFN12 heterotetramerPDE3A1-SERCA2-phospholamban-AKAP18 signalosome

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Three PDE3A isoforms exist in cardiac myocytes (PDE3A-136, PDE3A-118, PDE3A-94) differing in N-terminal sequence containing membrane-association domains and phosphorylation/activation sites for PKB and PKA. PDE3A-136 contains both membrane-association domains and PKB/PKA sites; PDE3A-118 contains only the downstream membrane-association domain and PKA sites; PDE3A-94 lacks both membrane localization domains and PKB/PKA sites. They are translated from two mRNAs derived from the PDE3A1 gene via alternative transcriptional and post-transcriptional processing. Antibodies to different regions of PDE3A, Western blotting, in vitro transcription/translation The Journal of biological chemistry High 12154085
2006 PKB/Akt phosphorylates PDE3A and activates its cAMP-hydrolytic activity. Phosphorylation of serines 290-292 is required for PKB/Akt-dependent activation of PDE3A and for PKB/Akt-induced meiotic maturation of both Xenopus and mouse oocytes. Microinjection of constitutively active Myr-Akt into mouse oocytes causes meiotic maturation in a PDE3A-dependent manner. Cell-free kinase assay with recombinant PKB/Akt and PKA, co-expression in Xenopus oocytes, serine-to-alanine mutagenesis, microinjection of myr-Akt into mouse oocytes, pde3a(-/-) rescue assays The EMBO journal High 17124499
1998 PDE3A in rat vascular smooth muscle cells is expressed as a 120 kDa protein found only in the cytosolic fraction, whereas PDE3B is expressed as a 135 kDa protein restricted to the particulate fraction. Prolonged incubation with cAMP-elevating agents (forskolin or 8-bromo-cAMP) produced time-dependent increases in PDE3 activity correlating with increased PDE3A and PDE3B signals and a marked increase in particulate PDE3 activity. RT-PCR with isoform-specific primers, immunoblotting with PDE3-selective antisera, subcellular fractionation British journal of pharmacology Medium 9884079
2015 PDE3A1 forms a multiprotein signalosome in human sarcoplasmic reticulum (SR) with SERCA2, phospholamban (PLB), and AKAP18. PKA phosphorylation of PDE3A increases its cAMP-hydrolytic activity, promotes its association with SERCA2/AKAP18 signalosomes, and modulates PLB phosphorylation and SERCA2 activity. Ser-292/Ser-293, a site unique to PDE3A1, is the principal site regulating interaction with SERCA2. Deletion of the PDE3A1/PDE3A2 N-terminus blocks interactions with SERCA2. Co-immunoprecipitation of endogenous and recombinant proteins, gel filtration chromatography, PKA phosphorylation assays, serine-to-alanine substitution mutagenesis, N-terminal deletion mutants, immunohistochemical staining, SERCA2 activity assay The Journal of biological chemistry High 25593322
2015 PDE3A gain-of-function missense mutations (six families) cause autosomal dominant hypertension with brachydactyly. The mutations increase PKA-mediated phosphorylation of PDE3A, resulting in increased cAMP-hydrolytic activity and enhanced cell proliferation in mesenchymal stem cell-derived VSMCs and chondrocytes. Levels of phosphorylated VASP were diminished and PTHrP levels were dysregulated. In vitro analyses of mesenchymal stem cell-derived VSMCs and chondrocytes, cAMP-hydrolytic activity assays, phosphorylation assays, VASP phosphorylation measurement, PTHrP measurement Nature genetics High 25961942
2015 DNMDP binding to PDE3A promotes a neomorphic interaction between PDE3A and Schlafen 12 (SLFN12). Co-expression of SLFN12 with PDE3A correlates with cancer cell sensitivity to DNMDP; depletion of either PDE3A or SLFN12 confers DNMDP resistance. PDE3A depletion alone also causes resistance. Phenotypic compound library screening across 766 cancer cell lines, target deconvolution by predictive chemogenomics, PDE3A depletion (knockdown), SLFN12 depletion, correlation of PDE3A gene expression with compound sensitivity Nature chemical biology High 26656089
2021 PDE3A and SLFN12 form a heterotetramer stabilized by DNMDP binding. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, further stabilized by SLFN12-DNMDP interactions. PDE3A binding activates SLFN12 RNase activity, and this RNase activity is required for DNMDP-induced cytotoxicity. Cryo-EM structure of PDE3A-SLFN12 complex, mutagenesis of interaction interface, SLFN12 RNase activity assay, cell viability assay with RNase-dead SLFN12 mutants Nature communications High 34272366
2021 High-resolution cryo-EM structures of PDE3A-SLFN12 complexes with anagrelide, nauclefine, or DNMDP show a butterfly-shaped heterotetramer. Small molecules are packed in a shallow pocket in the catalytic domain of PDE3A, and the resulting compound-modified interface binds the short helix (E552-I558) of SLFN12 through hydrophobic interactions, gluing the two proteins together. SLFN12 blocks protein translation leading to apoptosis. Cryo-EM structure determination from HeLa cells pre-treated with molecular glues, structure-guided analog synthesis, cell viability and apoptosis assays, tumor xenograft experiments Nature communications High 34707099
2009 Platelet agonists (including thrombin via PAR-1) stimulate PKC-dependent phosphorylation of PDE3A on Ser-312, Ser-428, Ser-438, Ser-465, and Ser-492, leading to increased cAMP hydrolysis and 14-3-3 protein binding. This phosphorylation and PDE3A activation required PKC but not PI3K/PKB, mTOR/p70S6K, or ERK/RSK. IGF-1, which activates PI3K/PKB but not PKC, did not regulate PDE3A. Phosphoproteomics/mass spectrometry mapping of phosphorylation sites, PKC inhibitors and phorbol ester activation, immunoprecipitation of 14-3-3/PDE3A complex, cAMP hydrolysis activity assay, platelet activation assays The Journal of biological chemistry High 19261611
2002 PKA stimulates phosphorylation and activation of PDE3A in gastric smooth muscle cells. Sodium nitroprusside (via cGMP) inhibits PDE3 activity and augments cAMP levels; this PDE3 inhibition is reversed by blockade of cGMP synthesis, demonstrating cGMP-mediated inhibition of PDE3A. RT-PCR and Western blot for PDE3A/PDE3B expression, PDE3A phosphorylation assay with PKA activators and inhibitors (PKI, H-89, KT-5823), PDE3 activity assay, cAMP measurement American journal of physiology. Cell physiology Medium 11832336
2011 PDE3A deletion in murine VSMCs suppresses MAPK signaling via two complementary pathways: PKA-catalyzed inhibitory phosphorylation of Raf-1 (Ser-259) with resulting ERK inhibition, and PKA/CREB-mediated induction of p21, leading to G0/G1 cell cycle arrest. PDE3A-KO VSMCs also showed elevated p53 accumulation, increased MKP-1, lower Cyclin-D1, and reduced Rb phosphorylation. p53 siRNA in 3A-KO VSMCs restored growth without affecting Cyclin-D1/Rb phosphorylation; dominant-negative CREB partially restored growth. PDE3A-KO mouse-derived VSMCs, serum/PDGF-induced DNA synthesis assay, ERK and Raf-1 phosphorylation analysis, cell cycle analysis, adenoviral overexpression of CREB constructs, p53 siRNA transfection The Journal of biological chemistry High 21632535
2010 PDE3A physically and functionally interacts with CFTR channel at the plasma membrane. PDE3A inhibition generates compartmentalized cAMP that clusters PDE3A and CFTR into plasma membrane microdomains and potentiates CFTR channel function. Actin skeleton disruption reduces PDE3A-CFTR interaction and compromises compartmentalized cAMP signaling and CFTR channel activation. Co-immunoprecipitation of PDE3A and CFTR, patch-clamp electrophysiology, actin disruption experiments, pig trachea submucosal gland secretion model Molecular biology of the cell Medium 20089840
2001 Mouse oocytes express a soluble form of PDE3A. Full-length recombinant PDE3A partitions to the particulate fraction, while N-terminal truncation forms (Delta 1 and Delta 2) are recovered mostly in the soluble fraction, identifying the N-terminus as the membrane-targeting domain. The Km values for cAMP hydrolysis by truncated forms are similar to those of full-length PDE3A (0.2-0.5 μM). cDNA cloning from mouse oocyte library, expression in Leydig tumor cells, subcellular fractionation, kinetic analysis, pharmacological profiling of recombinant enzyme vs oocyte PDE Biology of reproduction Medium 11420239
2000 Conserved histidines H752, H756, and glutamate E825 in the first metal-binding motif are essential for PDE3A catalytic activity (kcat near zero when mutated to alanine). E866A mutation increases Km for cAMP 11-fold and Ki for cGMP 27-fold, suggesting a role in substrate/inhibitor binding. H836A mutation raises Ki for cGMP 177-fold. cAMP and cGMP binding sites in PDE3A are overlapping but not identical, involving common and different amino acids. Site-directed mutagenesis, baculovirus/Sf9 expression, kinetic analysis (kcat, Km, Ki determination), metal ion-free assay supplemented with Mn2+, Mg2+, or Co2+ Blood High 10828019
1996 The PDE3A catalytic domain is localized to within amino acid residues 679-1141. Deletion mutants encoding residues 665-1141 and 679-1141 display PDE activity, while those starting at residue 686 or later lose detectable activity. Deletion mutagenesis, expression in PDE-deficient yeast (Saccharomyces cerevisiae), PDE activity assay, Western blotting Blood Medium 8695850
1998 Histidine H840 (second histidine in HDXXH motif) is essential for PDE3A catalytic activity (mutation to alanine abolishes activity), likely required for bivalent cation binding. H869A mutation reduces affinity for cAMP and cGMP (4-fold increases in Km and IC50 for cGMP), identifying it as part of the inhibitory binding site. Cysteine C816 (in the 44-aa insert unique to PDE3) is required for proper protein folding. Site-directed mutagenesis, expression in PDE-deficient yeast, kinetic analysis (kcat, Km, IC50 for cGMP and milrinone), Western blotting Archives of biochemistry and biophysics Medium 9826434
2013 PDE3A1 and PDE3A2 isoforms are selectively phosphorylated through different signaling pathways with distinct functional consequences. Isoproterenol (PKA activation) phosphorylates PDE3A1 at S312 (14-3-3-binding site), while PMA (PKC activation) phosphorylates PDE3A2 at alternative 14-3-3-binding site S428. PDE3A2 activity is stimulated by phosphorylation at S428, whereas PDE3A1 activity is not affected by phosphorylation at either site. The two isoforms have distinct protein interactomes revealed by 2D electrophoresis of co-immunoprecipitated proteins. FLAG-tagged PDE3A1 and PDE3A2 expression in HEK293 cells, gel filtration chromatography, 2D electrophoresis, co-immunoprecipitation, phospho-specific analysis with isoproterenol and PMA, PDE activity assay Proceedings of the National Academy of Sciences of the United States of America High 24248367
2010 In PDE3A(-/-) oocytes arrested at G2/M, elevated PKA activity is associated with inactivation of Cdc2 and Plk1, and inhibition of histone H3 (S10) phosphorylation and dephosphorylation of Cdc25B (S323) and Cdc2 (Thr14/Tyr15). PKAc phosphorylates recombinant Plk1 and inhibits Plk1 activity in vitro. PDE3A co-localizes with and co-immunoprecipitates with Plk1 in WT ovary and HeLa cells. PKA inhibitor (Rp-cAMPS) reactivates Plk1 in PDE3A(-/-) oocytes. PDE3A(-/-) mouse model, co-immunoprecipitation, co-localization imaging, in vitro Plk1 phosphorylation assay with recombinant PKAc, PKA inhibitor rescue experiment Cell cycle (Georgetown, Tex.) Medium 21099356
2016 PDE3A hydrolyzes cUMP with a Km of ~143 μM and Vmax of ~42 μmol/min/mg (low-affinity, high-velocity substrate). For comparison, cAMP is hydrolyzed with Km ~0.7 μM and Vmax ~1.2 μmol/min/mg. The PDE3 inhibitor milrinone inhibits cUMP hydrolysis (Ki = 57 nM). Enzyme kinetics (Michaelis-Menten analysis), HPLC-tandem mass spectrometry measurement of UMP and AMP formation, milrinone inhibition assay Naunyn-Schmiedeberg's archives of pharmacology Medium 27975297
2015 PDE3A-IBMX-resin chemical proteomics in HeLa cells identified 14-3-3 proteins as PDE3A interactors, and revealed that PDE3A associates with a PP2A complex composed of regulatory, scaffold, and catalytic subunits. Chemical proteomics with IBMX-based affinity resin, selective competition with cilostamide and papaverine, mass spectrometry identification of co-captured proteins in HeLa cell lysates Molecular bioSystems Medium 26205238
2017 SFPQ (splicing factor proline and glutamine rich) protein modulates PDE3A mRNA levels and functions as a transcriptional activator of PDE3A. Multiple transcription start sites (TSS1, 2, 3) were identified within the first exon of PDE3A. Serum-induced PDE3A expression was affected by increasing SFPQ binding to the upstream regulatory region, as demonstrated by ChIP-seq. 5'-RACE to map transcription start sites, ChIP-seq for SFPQ binding sites, SFPQ overexpression/knockdown with mRNA measurement, RT-PCR Bioscience reports Medium 28743736
2019 ATF3 transcription factor binds to a 29-nucleotide insertion (INS) in the PDE3A promoter and represses cAMP-dependent promoter activity. The INS also represses a cAMP response element enhancer 61 nt downstream. In failing hearts homozygous for the DEL genotype treated with PDE3 inhibitors, PDE3A1 mRNA and microsomal PDE3 enzyme activity were increased ~1.7-1.8 fold, consistent with derepression of the cAMP response element. Luciferase reporter assay with cloned PDE3A promoter variants, transcription factor binding analysis (ATF3), RT-PCR of explanted failing LVs, PDE3 enzyme activity measurement Journal of the American College of Cardiology Medium 30871701
2020 In human pulmonary artery smooth muscle cells (hPASMC), nitric oxide (NO) increases PDE3A protein expression and PDE3 activity via the soluble guanylate cyclase (sGC)-cGMP pathway, leading to decreased cAMP and activation of AMPK. Knockdown of PDE3A with siRNA blunts NO-induced AMPK activation, demonstrating PDE3A as an intermediary between NO/cGMP signaling and AMPK regulation. siRNA knockdown of PDE3A in hPASMC, Western blotting for AMPK phosphorylation, cAMP measurement, sGC stimulator and inhibitor pharmacology, PDE3 activity assay Physiological reports Medium 32914566
2022 Cytotoxic PDE3A modulators (molecular glues) promote PDE3A-SLFN12 interaction, increasing SLFN12 protein stability in the cytoplasm and inducing SLFN12 dephosphorylation at Ser-368 and Ser-573. This dephosphorylation is required for cell death. Dephosphorylation promotes the rRNA RNase activity of SLFN12, which is essential for SLFN12's cell-death-inducing function. Mutational analysis of SLFN12 phosphorylation sites, co-immunoprecipitation, cell death assays, SLFN12 RNase activity assay, protein stability assays Cell chemical biology High 35104454
2001 A vascular smooth muscle cell-specific PDE3A isoform ('PDE3A2') lacks the N-terminal 145 amino acids present in the myocardial isoform (PDE3A1) and is a product of the same gene, generated pre-translationally. The recombinant protein has a molecular mass of ~131 kDa, consistent with translation from an ATG at nt 436-438 of the myocardial PDE3A coding region. cDNA cloning from aortic myocytes, RT-PCR, 5'-RACE, RNase protection assay, Sf9 cell expression, Western blotting with region-specific antibodies The Biochemical journal Medium 11115397

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nature genetics 127 25961942
2002 Isoforms of cyclic nucleotide phosphodiesterase PDE3A in cardiac myocytes. The Journal of biological chemistry 107 12154085
2006 Protein kinase B/Akt phosphorylation of PDE3A and its role in mammalian oocyte maturation. The EMBO journal 101 17124499
1998 Expression of cyclic GMP-inhibited phosphodiesterases 3A and 3B (PDE3A and PDE3B) in rat tissues: differential subcellular localization and regulated expression by cyclic AMP. British journal of pharmacology 96 9884079
2015 Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2. The Journal of biological chemistry 84 25593322
2015 Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics. Nature chemical biology 82 26656089
2009 Protein kinase C-mediated phosphorylation and activation of PDE3A regulate cAMP levels in human platelets. The Journal of biological chemistry 81 19261611
2015 Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury. Proceedings of the National Academy of Sciences of the United States of America 74 25877153
2021 Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase. Nature communications 73 34272366
2002 PKA-dependent activation of PDE3A and PDE4 and inhibition of adenylyl cyclase V/VI in smooth muscle. American journal of physiology. Cell physiology 69 11832336
2011 Phosphodiesterase 3A (PDE3A) deletion suppresses proliferation of cultured murine vascular smooth muscle cells (VSMCs) via inhibition of mitogen-activated protein kinase (MAPK) signaling and alterations in critical cell cycle regulatory proteins. The Journal of biological chemistry 65 21632535
2010 Compartmentalized cyclic adenosine 3',5'-monophosphate at the plasma membrane clusters PDE3A and cystic fibrosis transmembrane conductance regulator into microdomains. Molecular biology of the cell 63 20089840
2001 Cloning and characterization of the cyclic guanosine monophosphate-inhibited phosphodiesterase PDE3A expressed in mouse oocyte. Biology of reproduction 62 11420239
2013 GWAS replication study confirms the association of PDE3A-SLCO1C1 with anti-TNF therapy response in rheumatoid arthritis. Pharmacogenomics 59 23651021
2001 Identification of a novel isoform of the cyclic-nucleotide phosphodiesterase PDE3A expressed in vascular smooth-muscle myocytes. The Biochemical journal 42 11115397
2021 Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells. Nature communications 41 34707099
1996 Human platelet cGI-PDE: expression in yeast and localization of the catalytic domain by deletion mutagenesis. Blood 40 8695850
2013 Selective regulation of cyclic nucleotide phosphodiesterase PDE3A isoforms. Proceedings of the National Academy of Sciences of the United States of America 33 24248367
2011 Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility. Current opinion in pharmacology 33 22051884
2019 miRNA-27a-3p and miRNA-222-3p as Novel Modulators of Phosphodiesterase 3a (PDE3A) in Cerebral Microvascular Endothelial Cells. Molecular neurobiology 31 30603956
2019 PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth. American journal of cancer research 26 31598394
2022 Multiple PDE3A modulators act as molecular glues promoting PDE3A-SLFN12 interaction and induce SLFN12 dephosphorylation and cell death. Cell chemical biology 25 35104454
2019 Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing. ACS medicinal chemistry letters 25 31749907
2000 Conserved amino acids in metal-binding motifs of PDE3A are involved in substrate and inhibitor binding. Blood 25 10828019
1996 Molecular cloning and chromosomal assignment of the human homologue of the rat cGMP-inhibited phosphodiesterase 1 (PDE3A)--a gene involved in fat metabolism located at 11p 15.1. Genomics 25 8921398
2020 Di (2-ethylhexyl) phthalate impairs primordial follicle assembly by increasing PDE3A expression in oocytes. Environmental pollution (Barking, Essex : 1987) 24 33234378
2016 A PDE3A mutation in familial hypertension and brachydactyly syndrome. Journal of human genetics 24 27053290
2019 Phosphodiesterase type 3A (PDE3A), but not type 3B (PDE3B), contributes to the adverse cardiac remodeling induced by pressure overload. Journal of molecular and cellular cardiology 23 31051182
2019 A PDE3A Promoter Polymorphism Regulates cAMP-Induced Transcriptional Activity in Failing Human Myocardium. Journal of the American College of Cardiology 19 30871701
2020 Nitric oxide activates AMPK by modulating PDE3A in human pulmonary artery smooth muscle cells. Physiological reports 17 32914566
2017 PDE3A is hypermethylated in cisplatin resistant non-small cell lung cancer cells and is a modulator of chemotherapy response. European review for medical and pharmacological sciences 16 28678321
1998 Partial characterization of the active site human platelet cAMP phosphodiesterase, PDE3A, by site-directed mutagenesis. Archives of biochemistry and biophysics 16 9826434
2000 Cardiac type cGMP-inhibited phosphodiesterase (PDE3A) gene structure: similarity and difference to adipocyte type PDE3B gene. Biochemical and biophysical research communications 15 10679291
2010 Female infertility in PDE3A(-/-) mice: polo-like kinase 1 (Plk1) may be a target of protein kinase A (PKA) and involved in meiotic arrest of oocytes from PDE3A(-/-) mice. Cell cycle (Georgetown, Tex.) 14 21099356
1998 Downregulation of right ventricular phosphodiesterase PDE-3A mRNA and protein before the development of canine heart failure. Cell biochemistry and biophysics 14 9631239
2023 Mutations in Phosphodiesterase 3A (PDE3A) Cause Hypertension Without Cardiac Damage. Hypertension (Dallas, Tex. : 1979) 13 37035914
2023 ETV1 inhibition depressed M2 polarization of tumor-associated macrophage and cell process in gastrointestinal stromal tumor via down-regulating PDE3A. Journal of clinical biochemistry and nutrition 12 36936869
2019 Electroacupuncture promotes the gastrointestinal motility of diabetic mice by CNP/NPR-B-cGMP and PDE3A-cGMP signaling. Neurogastroenterology and motility 12 30672071
2018 Lack of microRNA-155 ameliorates renal fibrosis by targeting PDE3A/TGF-β1/Smad signaling in mice with obstructive nephropathy. Cell biology international 12 30080287
2015 Hypertension linked to PDE3A activation. Nature genetics 12 26018892
2020 Hypertension and Brachydactyly Syndrome Associated With Vertebral Artery Malformation Caused by a PDE3A Missense Mutation. American journal of hypertension 10 31549136
2019 High cGMP and low PDE3A activity are associated with oocyte meiotic incompetence. Cell cycle (Georgetown, Tex.) 10 31401933
1998 Cyclic nucleotide PDE-3. Quantitation of PDE-3A and -3B mRNAs in rat tissues by RNase protection assay. Cell biochemistry and biophysics 10 9631238
2024 First-in-Human Dose-Escalation Study of the First-in-Class PDE3A-SLFN12 Complex Inducer BAY 2666605 in Patients with Advanced Solid Tumors Coexpressing SLFN12 and PDE3A. Clinical cancer research : an official journal of the American Association for Cancer Research 9 39437010
2018 PDE3A gene screening improves diagnostics for patients with Bilginturan syndrome (hypertension and brachydactyly syndrome). Hypertension research : official journal of the Japanese Society of Hypertension 9 30209282
2017 SFPQ, a multifunctional nuclear protein, regulates the transcription of PDE3A. Bioscience reports 9 28743736
2016 cUMP hydrolysis by PDE3A. Naunyn-Schmiedeberg's archives of pharmacology 9 27975297
2024 A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 7 38864850
2024 Velcrin molecular glues induce apoptosis in glioblastomas with high PDE3A and SLFN12 expression. Neuro-oncology advances 7 39166256
2024 Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia. Leukemia 7 39406931
2020 Identification and functional study of genetic polymorphisms in cyclic nucleotide phosphodiesterase 3A (PDE3A). Annals of human genetics 7 33249558
2017 Docking and quantitative structure-activity relationship of bi-cyclic heteroaromatic pyridazinone and pyrazolone derivatives as phosphodiesterase 3A (PDE3A) inhibitors. PloS one 7 29216268
2015 Charting the interactome of PDE3A in human cells using an IBMX based chemical proteomics approach. Molecular bioSystems 7 26205238
2024 Discovery of BAY 2666605, a Molecular Glue for PDE3A and SLFN12. ACS medicinal chemistry letters 6 39411532
2024 Pde3a and Pde3b regulation of murine pulmonary artery smooth muscle cell growth and metabolism. Physiological reports 6 39435735
2014 PDE3A-SLCO1C1 locus is associated with response to anti-tumor necrosis factor therapy in psoriatic arthritis. Pharmacogenomics 6 25493569
1992 Insulin and isoproterenol induce phosphorylation of the particulate cyclic GMP-inhibited, low Km cyclic AMP phosphodiesterase (cGI PDE) in 3T3-L1 adipocytes. Biochemical and biophysical research communications 6 1314573
2023 PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma. Cancers 5 38001568
2016 Synthesis of linear and angular aryl-morpholino-naphth-oxazines, their DNA-PK, PI3K, PDE3A and antiplatelet activity. Bioorganic & medicinal chemistry letters 5 27765510
2024 ALDOA coordinates PDE3A through the β-catenin/ID3 axis to stimulate cancer metastasis and M2 polarization in lung cancer with EGFR mutations. Biochemical and biophysical research communications 4 38244313
2023 PDE3A and GSK3B as Atrial Fibrillation Susceptibility Genes in the Chinese Population via Bioinformatics and Genome-Wide Association Analysis. Biomedicines 4 36979891
2023 CRISPR/Cas9 Knock-Out in Primary Neonatal and Adult Cardiomyocytes Reveals Distinct cAMP Dynamics Regulation by Various PDE2A and PDE3A Isoforms. Cells 4 37296663
2019 PDE3A variant associated with hypertension and brachydactyly syndrome in a patient with ischemic stroke caused by spontaneous intracranial artery dissection: A review of the clinical and molecular genetic features. European journal of medical genetics 4 31589936
2017 Synthesis and biological evaluation of 8-aryl-2-morpholino-7-O-substituted benzo[e][1,3]oxazin-4-ones against DNA-PK, PI3K, PDE3A enzymes and platelet aggregation. Bioorganic & medicinal chemistry 4 28838830
2025 PDE3A as a Therapeutic Target for the Modulation of Compartmentalised Cyclic Nucleotide-Dependent Signalling. Cells 2 40497949
2020 Whole-exome sequencing identifies a de novo PDE3A variant causing autosomal dominant hypertension with brachydactyly type E syndrome: a case report. BMC medical genetics 2 32631253
2025 IGF2BP3 Modulates mRNA Splicing and Stability to Promote Trophoblast Progression via Interaction with PDE3A and Suppression by miR-196a-5p in Preeclampsia. Biomedicines 1 40563987
2026 AR-mediated YBX3 suppresses oocyte meiotic resumption in polycystic ovary syndrome by attenuating Pde3A and Ccnb1 expression. Journal of ovarian research 0 41673703
2026 The Role of PDE3A in Cancer. ACS omega 0 41726589
2026 Pan-cancer ex vivo target evaluation of phosphodiesterase 3 A (PDE3A). Journal of molecular medicine (Berlin, Germany) 0 42047795
2024 RETRACTION: Lack of MicroRNA-155 Ameliorates Renal Fibrosis by Targeting PDE3A/TGF-β1/Smad Signaling in Mice with Obstructive Nephropathy. Cell biology international 0 38845116

Missed literature

Know a paper Affinage missed for PDE3A? Flag it for the maintainers and the community.

No submissions yet.