Affinage

PDE4B

3',5'-cyclic-AMP phosphodiesterase 4B · UniProt Q07343

Length
736 aa
Mass
83.3 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDE4B is a cAMP-specific phosphodiesterase that hydrolyzes cAMP to shape spatially restricted cAMP/PKA signaling and thereby controls innate and adaptive immunity, cardiac beta-adrenergic responses, and synaptic plasticity (PMID:21288894, PMID:12032334, PMID:32264695, PMID:21458469). Its three human splice variants differ in their unique N-terminal regions, which dictate cytosolic versus particulate distribution, maximal hydrolytic activity, and rolipram sensitivity (PMID:9371714). Functionally, PDE4B governs cAMP within a near-membrane subdomain rather than the bulk cytosol, selectively gating Toll-like receptor signaling while sparing CREB-mediated transcription (PMID:21288894). In resting cells PDE4B is sequestered through binding of its UCR2 domain to the scaffold DISC1, from which it is released and activated upon cAMP elevation; DISC1 organizes PDE4B together with NDE1, NDEL1, LIS1, and dynein at the centrosome and synapses, coupling local cAMP hydrolysis to PKA-dependent NDE1 phosphorylation (PMID:16293762, PMID:18983980). Co-crystal structures define how selective inhibitors act, either by displacing the invariant Gln-443 and shifting helix-15 or by engaging a C-terminal regulatory helix (CR3) to lock the enzyme in a closed, inactive conformation (PMID:19525117, PMID:24998378). In immunity, PDE4B is required for LPS-induced TNF-alpha production and is transcriptionally induced as a feedback regulator by LPS via PKA-Cbeta/NF-kappaB p65 (Ser276) cross-talk and by IL-2/STAT5, with inhibition suppressing inflammation through JNK2-dependent induction of the deubiquitinase CYLD (PMID:12032334, PMID:25831493, PMID:23451206, PMID:23575688). PDE4B protein levels are controlled by Smurf2-mediated ubiquitination and degradation, which is blocked by the circular RNA circDlg1 acting through PDE4B's N-terminal targeting domain to maintain low cAMP and dampen anti-inflammatory PKA/CREB signaling in microglia (PMID:29100790, PMID:40093898). In the heart, PDE4B blunts beta-adrenergic cAMP/PKA signaling, L-type Ca2+ current, and contraction, and protects against catecholamine- and pressure-overload-induced dysfunction, while also driving neutrophil-endothelial interactions in ischemia-reperfusion injury (PMID:32264695, PMID:35899614). In B-cell lymphoma, PDE4B inactivates cAMP to abrogate apoptosis through a PKA/EPAC-independent, PI3K/AKT-linked mechanism and participates in a mutually reinforcing feed-forward loop with MYC (PMID:15331441, PMID:31138843).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1997 High

    Established that PDE4B is not a single activity but a set of splice variants whose unique N-termini determine where the enzyme localizes and how it behaves enzymatically and pharmacologically.

    Evidence Cloning and expression of HSPDE4B1/2/3 in COS7 cells with fractionation, cAMP hydrolysis, and rolipram inhibition assays

    PMID:9371714

    Open questions at the time
    • Did not resolve isoform-specific signaling partners in vivo
    • N-terminal targeting determinants not mapped at residue level
  2. 2002 High

    Answered whether a specific PDE4 isoform controls innate immune cytokine output by showing PDE4B, not PDE4D, is required for LPS-driven TNF-alpha and is itself induced as feedback.

    Evidence PDE4B knockout mice with LPS stimulation, cytokine mRNA/protein, and PDE4 activity assays in macrophages and leukocytes

    PMID:12032334

    Open questions at the time
    • Did not define the transcriptional pathway inducing PDE4B
    • Compartment of cAMP control not yet identified
  3. 2004 High

    Showed how PDE4B promotes lymphoma survival by hydrolyzing pro-apoptotic cAMP through a PKA/EPAC-independent, PI3K/AKT-linked route.

    Evidence DLBCL cell lines reconstituted with wild-type/mutant PDE4B, cAMP-induced apoptosis assays, and constitutively active AKT epistasis

    PMID:15331441

    Open questions at the time
    • Mechanistic link between cAMP and AKT not fully defined
    • Did not address upstream regulation of PDE4B in lymphoma
  4. 2005 High

    Defined the regulatory logic of PDE4B activation by showing DISC1 sequesters it via UCR2 and releases it upon cAMP elevation, coupling scaffold binding to enzyme activity.

    Evidence Co-immunoprecipitation, UCR2 domain mapping, and cellular cAMP elevation assays

    PMID:16293762

    Open questions at the time
    • Structural basis of UCR2-DISC1 interface not solved
    • Did not establish physiological cAMP threshold for dissociation
  5. 2008 Medium

    Extended the DISC1-PDE4B relationship into a multiprotein scaffold linking local cAMP hydrolysis to PKA phosphorylation of NDE1 at the centrosome and synapses.

    Evidence Co-immunoprecipitation and immunofluorescence in cultured neurons for DISC1/NDE1/NDEL1/LIS1/dynein/PDE4B

    PMID:18983980

    Open questions at the time
    • Scaffold stoichiometry inferred, not measured
    • Direct versus indirect interactions within the complex not resolved
  6. 2011 High

    Resolved where PDE4B acts by demonstrating it controls cAMP in a near-membrane subdomain that selectively gates TLR signaling without affecting bulk cytosolic cAMP or CREB transcription.

    Evidence PDE4B/PDE4D gene ablation in MEFs with FRET cAMP reporters, phosphoprotein, and transcription reporter assays

    PMID:21288894

    Open questions at the time
    • Molecular anchors tethering PDE4B near the membrane not identified
    • Did not extend compartment mapping to immune cell types
  7. 2011 Medium

    Tied PDE4B function to synaptic plasticity and cognition by showing loss enhances hippocampal LTD and impairs reversal learning.

    Evidence PDE4B knockout mice with hippocampal slice electrophysiology and Morris water maze

    PMID:21458469

    Open questions at the time
    • Cell-type and isoform responsible not dissected
    • cAMP/PKA effectors mediating LTD change not defined
  8. 2011 Medium

    Showed DISC1 can co-assemble PDE4B and GSK-3, and that a DISC1 variant reshapes this complex, linking genetic variation to convergent cAMP/GSK-3 signaling.

    Evidence DISC1 Q31L/L100P mutant mice with GSK-3 activity, binding assays, and rolipram/TDZD-8 pharmacological epistasis

    PMID:21376063

    Open questions at the time
    • Direct ternary complex not structurally demonstrated
    • Functional output of converged signaling in vivo incomplete
  9. 2009 High

    Provided a structural mechanism for inhibition by showing a THBT inhibitor displaces the invariant Gln-443 and shifts helix-15.

    Evidence X-ray co-crystal structure of THBT inhibitor with PDE4B

    PMID:19525117

    Open questions at the time
    • Did not establish isoform selectivity in cells
    • Conformational dynamics under physiological regulation not addressed
  10. 2014 High

    Defined a distinct inhibitor mechanism in which triazines engage a C-terminal regulatory helix (CR3) to lock PDE4B in an inactive closed state, enabling subtype-selective design.

    Evidence High-resolution co-crystal structures with SAR analysis

    PMID:24998378

    Open questions at the time
    • Whether CR3 engagement occurs with endogenous regulators unknown
    • Selectivity over other PDE4 subtypes not validated in vivo
  11. 2013 High

    Explained an anti-inflammatory mechanism of PDE4B inhibition through JNK2-selective induction of the deubiquitinase CYLD.

    Evidence PDE4 inhibitor treatment, JNK1/JNK2 selective activation, and CYLD-knockout mouse epistasis

    PMID:23575688

    Open questions at the time
    • Connection between cAMP and JNK2 selectivity not detailed
    • Cell types mediating in vivo effect not fully resolved
  12. 2013 Medium

    Identified IL-2/STAT5 as a transcriptional inducer of PDE4B and revealed cell-type-restricted expression in CD8+ T cells with aberrant expression in lymphoid cancers.

    Evidence Microarray, STAT5 ChIP-on-chip, and qRT-PCR in PHA-activated human PBMCs

    PMID:23451206

    Open questions at the time
    • Functional consequence of STAT5-driven PDE4B in T cells not tested
    • Mechanism of aberrant CD4+ cancer expression unknown
  13. 2013 Medium

    Established a MYC-PDE4B feed-forward loop sustaining B-lymphoma proliferation and survival, identifying a combinatorial vulnerability.

    Evidence B-lymphoma lines, Emu-myc transgenic mice, co-inhibition, and xenograft experiments

    PMID:31138843

    Open questions at the time
    • Direct transcriptional wiring between MYC and PDE4B not mapped
    • Single-lab in vivo validation
  14. 2015 High

    Defined a transcriptional induction mechanism for PDE4B2 via PKA-Cbeta phosphorylation of NF-kappaB p65 at Ser276, with both enzymatic and non-enzymatic contributions to chemokine induction.

    Evidence In vitro/in vivo expression, PKA-Cbeta and p65 knockdown/overexpression, Ser276 mutagenesis, and promoter assays

    PMID:25831493

    Open questions at the time
    • Nature of the non-enzymatic chemokine contribution unresolved
    • Generality across stimuli beyond NTHi/roflumilast not tested
  15. 2017 Medium

    Identified Smurf2 as the E3 ligase driving ubiquitin-dependent PDE4B degradation, linking PDE4B turnover to cAMP-PKA-CREB output and downstream anti-fibrotic miR-132/CTGF signaling.

    Evidence Co-IP, transgenic overexpression/knockdown mice, miRNA array, and dual-luciferase assays

    PMID:29100790

    Open questions at the time
    • Ubiquitination site on PDE4B not mapped
    • Reciprocal validation of the Smurf2-PDE4B interaction limited
  16. 2025 Medium

    Showed circDlg1 stabilizes PDE4B by forming a ternary complex with Smurf2 through PDE4B's N-terminal targeting domain, sustaining low cAMP and impaired anti-inflammatory PKA/CREB signaling in microglia.

    Evidence RNA pulldown/MS, RIP, Co-IP, domain mapping, and AAV knockdown in APP/PS1 mice with behavior

    PMID:40093898

    Open questions at the time
    • Structural basis of the ternary complex not solved
    • Single-lab in vivo validation
  17. 2020 High

    Demonstrated PDE4B restrains cardiac beta-adrenergic cAMP/PKA signaling and Ca2+ handling, with moderate overexpression protecting against heart failure phenotypes.

    Evidence Cardiomyocyte-specific transgenic and AAV9 PDE4B mice with FRET imaging, patch-clamp, and isoproterenol/TAC disease models

    PMID:32264695

    Open questions at the time
    • Endogenous PDE4B compartmentation in cardiomyocytes not fully defined
    • Therapeutic window of overexpression not established
  18. 2020 High

    Showed PDE4B drives neutrophil-endothelial interactions and microvascular dysfunction in myocardial ischemia-reperfusion via PKA-dependent adhesion molecule expression, with NO-dependent vasodilatory effects upon blockade.

    Evidence PDE4B knockout mice with bone marrow chimeras, reperfusion model, and human coronary vasomotor assays

    PMID:35899614

    Open questions at the time
    • Cell-intrinsic versus endothelial contributions only partly separated
    • Adhesion molecule targets not exhaustively mapped
  19. 2016 Medium

    Linked PDE4B to neuroinflammation and gut-CNS crosstalk after spinal cord injury, with deletion reducing ER stress, inflammation, dysbiosis, and improving white matter sparing.

    Evidence Pde4b knockout mice with thoracic contusion SCI, molecular markers, microbiome sequencing, and locomotor recovery

    PMID:30557659

    Open questions at the time
    • Cellular source of pathogenic PDE4B in cord not defined
    • Causal direction of gut-CNS axis not fully established
  20. 2016 Medium

    Established a metabolic role for PDE4B in alcohol-induced hepatic steatosis through cAMP suppression of fatty-acid oxidation via the Pparalpha/Sirt1/Pgc1alpha axis.

    Evidence Pde4b knockout mice with alcohol feeding, hepatic cAMP and gene expression analysis, and rolipram treatment

    PMID:27287961

    Open questions at the time
    • Direct PDE4B target compartment in hepatocytes not defined
    • Isoform responsible not identified
  21. 2022 Medium

    Showed PDE4B is the dominant dendritic-cell phosphodiesterase acting as a PKA-dependent homeostatic cAMP buffer.

    Evidence Gas-depleted DC mouse model, PKA inhibitor experiments, and PDE4B inhibitor with T cell readouts

    PMID:35387344

    Open questions at the time
    • Transcriptional mechanism of homeostatic feedback not defined
    • Impact on antigen-specific responses limited
  22. 2021 Medium

    Identified NFATc2 as a required transcription factor for LPS-induced PDE4B in macrophages and tied its temporal dynamics to lung injury and reparative reprogramming.

    Evidence RNA-seq of sorted macrophages, NFATc2 inhibition, intratracheal rolipram, monocyte depletion, and adoptive transfer

    PMID:34318714

    Open questions at the time
    • Direct NFATc2 binding to the PDE4B locus not shown
    • Isoform induced not specified
  23. 2025 Medium

    Mapped a circuit-level role for Pde4b in stress-induced anxiety through cAMP signaling in an auditory-to-somatosensory GABAergic projection.

    Evidence Single-cell and spatial transcriptomics, targeted Pde4b knockdown, optogenetics/chemogenetics, and behavior

    PMID:39891910

    Open questions at the time
    • Downstream cAMP effectors in the circuit not defined
    • Isoform specificity not resolved
  24. 2024 Medium

    Provided genetic evidence that reduced PDE4B activity is protective in Alzheimer's models, with a hypomorphic Y358C allele preventing memory and metabolic deficits independent of amyloid.

    Evidence AppNL-G-F mice crossed with Pde4bY358C hypomorphs, Barnes maze, deoxyglucose autoradiography, and RNA-seq

    PMID:38521860

    Open questions at the time
    • Mechanism linking cAMP to the protective transcriptomic signature unclear
    • Relevance of identified DEGs not functionally tested
  25. 2024 Medium

    Connected a hypofunctional PDE4B missense variant (M220T) to PTSD-relevant behavior, linking attenuated cAMP hydrolysis to altered fear and sensorimotor gating.

    Evidence HEK-293 cAMP assays of PDE4B1-M220T and homozygous knock-in mice with behavioral battery

    PMID:39256048

    Open questions at the time
    • Circuit basis of the behavioral phenotype not localized
    • Human genetic association not established within this study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct PDE4B isoforms and their N-terminal targeting determinants are matched to specific cAMP microdomains, scaffolds, and effector outputs across tissues remains incompletely defined.
  • No unified map of isoform-specific anchoring partners across cell types
  • Endogenous structural state coupling regulation and catalysis not resolved
  • Whether selective inhibitor conformations recapitulate physiological regulation is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 2
Partners
DISC1GSK3LIS1NDE1NDEL1SMURF2
Complex memberships
DISC1-PDE4B-NDE1-NDEL1-LIS1-dynein scaffold complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 DISC1 physically interacts with the UCR2 domain of PDE4B, sequestering it in resting cells; elevation of cellular cAMP causes dissociation of PDE4B from DISC1 and an increase in PDE4B enzymatic activity. Co-immunoprecipitation, domain-mapping, cellular cAMP elevation assay Science High 16293762
2002 PDE4B (but not PDE4D) is required for LPS-induced TNF-alpha production in peripheral leukocytes and macrophages; LPS stimulation induces PDE4B mRNA accumulation and increases PDE4 enzymatic activity, constituting a feedback regulation essential for the innate immune response. PDE4B knockout mice, LPS stimulation, cytokine measurement (TNF-alpha mRNA and protein), PDE4 activity assay Proceedings of the National Academy of Sciences of the United States of America High 12032334
1997 Three human PDE4B splice variants (HSPDE4B1, HSPDE4B2, HSPDE4B3) differ in their unique N-terminal regions, subcellular distribution (cytosol vs. particulate fractions), maximal cAMP hydrolytic activity, and sensitivity to rolipram inhibition; the N-terminal splice region determines these isoform-specific properties. Molecular cloning, transient expression in COS7 cells, subcellular fractionation, cAMP hydrolysis assay, rolipram inhibition assay The Biochemical journal High 9371714
2004 PDE4B inactivates cAMP to abrogate cAMP-induced apoptosis in diffuse large B-cell lymphoma (DLBCL); this cAMP-mediated apoptosis is largely independent of PKA and EPAC but associated with inhibition of the PI3K/AKT pathway, with AKT centrally required as confirmed by constitutively active AKT mutants. DLBCL cell lines reconstituted with wild-type or mutant PDE4B, cAMP-induced apoptosis assay, PI3K/AKT pathway analysis, constitutively active AKT mutant expression Blood High 15331441
2008 DISC1, NDE1, NDEL1, LIS1, and dynein associate with PDE4B and PDE4D within cells; this complex localizes to the centrosome and to synapses in cultured neurons. NDE1 is phosphorylated by PKA whose activity is regulated by PDE4-mediated cAMP hydrolysis, suggesting DISC1 acts as a scaffold assembling these proteins. Co-immunoprecipitation, immunofluorescence localization in cultured neurons Biochemical and biophysical research communications Medium 18983980
2011 PDE4B controls cAMP specifically in a near-membrane subdomain in mouse embryonic fibroblasts; PDE4B ablation increases basal and hormone-dependent cAMP near the plasma membrane but not in bulk cytosol, and selectively affects Toll-like receptor signaling but not CREB-mediated transcription. PDE4B/PDE4D gene ablation in mouse embryonic fibroblasts, subcellular cAMP reporter assays (FRET-based), phosphoprotein analysis, transcription reporter assay The Journal of biological chemistry High 21288894
2009 Co-crystal structure of a tetrahydrobenzothiophene (THBT) inhibitor with PDE4B revealed an unprecedented binding mode in which the ligand displaces the invariant Gln-443 residue and shifts helix-15 by 1-2 Å; C-terminal residues previously proposed to confer subtype selectivity are resolved and extend into the ligand binding site. X-ray co-crystal structure determination Bioorganic & medicinal chemistry High 19525117
2014 High-resolution co-crystal structure of triazine PDE4B inhibitors shows that they interact with both the catalytic domain and a C-terminal regulatory helix (CR3), locking the enzyme in an inactive 'closed' conformation; this provides a structural basis for PDE4B-selective inhibitor design. X-ray co-crystal structure determination, structure-activity relationship analysis Bioorganic & medicinal chemistry letters High 24998378
2013 Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD; PDE4B negatively regulates CYLD via specific activation of JNK2 (but not JNK1); in CYLD-deficient mice, PDE4B inhibition no longer suppresses inflammation. PDE4 inhibitor treatment, CYLD expression assay, JNK1/JNK2 selective activation, CYLD-knockout mice Nature communications High 23575688
2015 Roflumilast synergizes with NTHi to up-regulate PDE4B2 expression via a PKA catalytic subunit β (PKA-Cβ) / NF-κB p65 cross-talk; PKA-Cβ phosphorylates p65 in a cAMP-dependent manner at Ser276, which is critical for synergistic PDE4B2 induction; up-regulated PDE4B2 contributes to chemokine induction in both enzymatic activity-dependent and -independent manners. In vitro and in vivo gene expression studies, PKA-Cβ and p65 knockdown/overexpression, site-directed mutagenesis (Ser276), promoter assays Proceedings of the National Academy of Sciences of the United States of America High 25831493
2017 Smurf2 (E3 ubiquitin ligase) interacts with PDE4B and facilitates its ubiquitination-dependent degradation, thereby activating the cAMP-PKA-CREB pathway; elevated cAMP increases miR-132 expression, which targets CTGF to suppress liver fibrosis. Co-immunoprecipitation, overexpression/knockdown in transgenic mice, miRNA array, dual-luciferase assay, western blot Biochimica et biophysica acta. Molecular cell research Medium 29100790
2025 CircDlg1 (a circular RNA) forms a ternary complex with PDE4B and Smurf2, blocking Smurf2-mediated ubiquitination and degradation of PDE4B via PDE4B's unique N-terminal targeting domain; elevated PDE4B reduces cAMP and suppresses PKA/CREB anti-inflammatory signaling in microglia. RNA pulldown, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation, AAV-mediated knockdown in APP/PS1 mice, behavioral testing Theranostics Medium 40093898
2020 PDE4B mediates neutrophil-endothelial cell interaction in myocardial ischemia-reperfusion (MI/R) injury via PKA-dependent expression of cell adhesion molecules, promotes neutrophil cardiac infiltration, and promotes coronary microcirculatory obstruction and vascular permeability; PDE4B blockade increases flow-mediated vasodilatation in a PKA- and nitric oxide-dependent manner. PDE4B knockout mice, bone marrow transplant (cell-specific rescue), coronary artery ligation/reperfusion model, laser Doppler flow, patch-clamp, vasomotor reactivity assays in mouse and human coronary arteries Circulation research High 35899614
2020 Cardiac overexpression of PDE4B blunts beta-adrenergic receptor stimulation of cAMP, PKA activity, L-type Ca2+ current, Ca2+ transients, and cell contraction; moderate PDE4B overexpression protects against isoproterenol- and pressure overload-induced systolic dysfunction, hypertrophy, fibrosis, and apoptosis. Transgenic mouse lines with cardiomyocyte-specific PDE4B overexpression, AAV9-PDE4B gene delivery, echocardiography, FRET-based cAMP and PKA imaging, whole-cell patch-clamp, isoproterenol infusion and transverse aortic constriction models Circulation High 32264695
2011 PDE4B and GSK-3 both bind the N-terminal region of DISC1 and can converge signals via DISC1 simultaneously; DISC1 Q31L mutation reduces PDE4B binding and increases GSK-3 enzymatic activity, demonstrating that DISC1 genetic variation influences the biochemical complex with PDE4B and GSK-3. Double-mutant DISC1 mouse models (Q31L and L100P), biochemical analysis of GSK-3 activity and DISC1 binding, pharmacological epistasis (rolipram + TDZD-8) Neuropharmacology Medium 21376063
2011 PDE4B knockout mice display enhanced long-term depression (LTD) and increased basal postsynaptic responses in hippocampal slices, but no change in LTP; behaviorally, PDE4B-/- mice show impaired reversal learning in the Morris water maze but normal spatial memory acquisition. PDE4B knockout mice, hippocampal slice electrophysiology (LTP/LTD protocols), Morris water maze Neuropharmacology Medium 21458469
2008 PDE4B knockout mice show decreased striatal dopamine and serotonin levels, decreased prepulse inhibition (PPI), decreased baseline locomotor activity, and an exaggerated locomotor response to high-dose amphetamine; PDE4B is required for normal PDE4 catalytic activity in multiple brain regions. PDE4B knockout mice, monoamine measurement, PPI assay, locomotor activity, amphetamine challenge Psychopharmacology Medium 18060387
2007 PDE4B mediates at least part of the antipsychotic-like effects of rolipram: rolipram suppresses conditioned avoidance responding (CAR) in wild-type mice but with a 3-fold shift in ED50 in PDE4B knockout mice, demonstrating PDE4B involvement in rolipram's mechanism of action. PDE4B knockout mice, conditioned avoidance responding assay, rolipram dose-response Psychopharmacology Medium 17333137
2016 PDE4B drives both acute local inflammatory response and chronic systemic inflammatory response after spinal cord injury; Pde4b deletion reduces markers of ER stress and inflammation at the injury site, increases oligodendrocyte mRNA expression, improves white matter sparing, and prevents SCI-induced gut dysbiosis and endotoxemia. Pde4b knockout mice, thoracic contusion SCI model, molecular markers (GFAP, CD11b, Iba1, Cox2), gut microbiome analysis, locomotor recovery assessment Neurobiology of disease Medium 30557659
2016 Alcohol feeding increases hepatic PDE4B expression, reduces cAMP levels, and impairs fatty acid oxidation via reduced Cpt1a expression through the Pparα/Sirt1/Pgc1α pathway; Pde4b knockout prevents alcohol-induced hepatic steatosis. Pde4b knockout mice, alcohol liquid diet feeding, hepatic cAMP measurement, gene expression analysis (Cpt1a, Pparα, Sirt1, Pgc1α), rolipram treatment The Journal of pathology Medium 27287961
2022 PDE4B is the primary phosphodiesterase expressed in dendritic cells (DCs) and acts as a homeostatic regulator of cAMP: its expression falls when cAMP decreases and rises when cAMP increases, in a PKA-dependent feedback manner. Gαs-depleted DC mouse model, PDE4B expression analysis, PKA inhibitor experiments, PDE4B inhibitor treatment with T cell response readout Frontiers in pharmacology Medium 35387344
2013 MYC and PDE4B mutually reinforce each other's expression in a feed-forward loop in B-cell lymphoma; combined targeting of Myc and PDE4 synergistically prevents B lymphoma cell proliferation and survival in vitro and in vivo. B-lymphoma cell lines, Eμ-myc transgenic mice, co-inhibition experiments, xenograft model, western blot for Myc/PDE4B expression Leukemia Medium 31138843
2013 IL-2 activates STAT5, which binds the PDE4B gene locus to transcriptionally induce PDE4B expression in activated human PBMCs; PDE4B is expressed in CD8+ but not CD4+ primary T cells, while lymphoid cancer CD4+ cells aberrantly express PDE4B. Affymetrix microarray, ChIP-on-chip STAT5 cistrome mapping, qRT-PCR validation in PHA-activated human PBMCs, protein expression analysis PloS one Medium 23451206
2018 PDE4B deficiency (Pde4b-/-) prevents SCI-induced gut dysbiosis, bacterial overgrowth, and endotoxemia, suggesting PDE4B links gut-CNS inflammation after spinal cord injury. Pde4b knockout mice, thoracic contusion SCI model, gut microbiome sequencing, endotoxin measurement Neurobiology of disease Medium 30557659
2021 PDE4B loss-of-function in sclera decreases cAMP and reduces collagen synthesis, leading to thinner collagen fibrils and myopia progression; inhibition of PDE4 with rolipram inhibits TGF-β2-induced collagen synthesis in human scleral fibroblasts. Pde4b knockout mice, form deprivation myopia model, scleral transcriptome sequencing, subconjunctival rolipram injection, electron microscopy of collagen fibrils, human scleral fibroblast culture Experimental eye research Medium 34506801
2022 JDP2 (transcription factor c-Jun dimerization protein 2) directly binds the PDE4B promoter and transcriptionally activates PDE4B expression in hypoxia/reoxygenation-injured cardiomyocytes; JDP2-driven PDE4B upregulation contributes to oxidative stress and apoptosis. Dual luciferase reporter assay, chromatin immunoprecipitation, siRNA knockdown, overexpression in H9c2 cardiomyocytes under H/R conditions Experimental and therapeutic medicine Medium 35401806
2025 Acute stress reduces Pde4b-regulated cAMP signaling in auditory GABAergic neurons projecting to somatosensory cortex Sst neurons (AUDGABA-S1TrSst circuit), leading to decreased S1TrSst neuron activity and anxiety-like behavior; targeted Pde4b knockdown in S1TrSst projections mimics this anxiety. Single-cell sequencing, spatial transcriptome sequencing, targeted Pde4b protein knockdown, optogenetics/chemogenetics of S1TrSst neurons, behavioral tests Cell reports Medium 39891910
2024 A hypomorphic PDE4B mutation (Y358C) that decreases cAMP hydrolytic activity prevents spatial memory deficits and brain metabolism impairments in the AppNL-G-F Alzheimer's disease mouse model without reducing amyloid plaque burden; transcriptomic analysis identified Ide, Btaf1, Padi2, and C1qb as differentially expressed genes relevant to this protective effect. AppNL-G-F knock-in mice crossed with Pde4bY358C hypomorphic mice, Barnes maze, 14C-2-deoxyglucose autoradiography, RNA sequencing Neuropsychopharmacology Medium 38521860
2024 PDE4B missense variant M220T (rs775201287) attenuates the PDE4B1 response to forskolin-elicited cAMP elevation in HEK-293 cells, and homozygous Pde4b M220T mice show increased BDNF expression, startle hyperreactivity, PPI deficits, altered fear conditioning, and enhanced persistence of traumatic memories consistent with PTSD-relevant phenotypes. HEK-293 cell cAMP assay with PDE4B1-M220T, homozygous knock-in mice, behavioral battery, cAMP pathway analysis The Journal of neuroscience Medium 39256048
2017 Attenuation of PDE4B1 activity (via D564A dominant-negative transgene in hippocampus/forebrain) increases CREB and ERK1/2 phosphorylation, enhances hippocampal neurogenesis, increases baseline synaptic transmission, and enhances LTP in male mice. PDE4B1-D564A dominant-negative transgenic mice, immunoblot for phospho-CREB/ERK, neurogenesis assay, hippocampal electrophysiology (LTP) BMC neuroscience Medium 29197324
2012 ZNF804a directly binds chromatin proximal to the promoter regions of PRSS16 and COMT, and its expression significantly decreases PDE4B transcript levels, indicating ZNF804a transcriptionally regulates PDE4B expression. ChIP assay, ZNF804a overexpression, qRT-PCR in neural progenitor cells PloS one Low 22384243
2005 During late-LTP induction in hippocampal slices, PDE4B protein changes are detected within the PSD-enriched fraction but FISH shows no translocation of PDE4B3 mRNA from soma, suggesting local post-translational modulation or protein translocation to activated synaptic structures regulates cAMP at synapses. Hippocampal slice LTP recording, subcellular fractionation, FISH, fluorescence imaging Brain research Low 15829230
2021 NFATc2 activation is required for LPS-induced transcription of PDE4b in macrophages; PDE4b expression peaks at time of peak lung injury then falls during resolution; inhibition of PDE4 activity at peak injury increases cAMP in alveolar macrophages and augments their reparative reprogramming from recruited monocytes. RNA-seq of flow-sorted macrophages, NFATc2 inhibition assay, intratracheal rolipram, conditional monocyte depletion, adoptive transfer of rolipram-educated macrophages, LysM-GFP mice American journal of physiology. Lung cellular and molecular physiology Medium 34318714
2025 PDE4B overexpression in nucleus pulposus cells upregulates ferroptosis markers (ACSL4, TFRC) and downregulates Nrf2, promoting ferroptosis and IDD pathogenesis; PDE4 inhibitor roflumilast reverses this process, with synergistic effect when combined with ferroptosis inhibitor. PDE4B overexpression in nucleus pulposus cells, in vivo rat IDD model, PDE4 inhibitor treatment, ferroptosis marker analysis Scientific reports Low 39893206

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science (New York, N.Y.) 523 16293762
2002 Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proceedings of the National Academy of Sciences of the United States of America 285 12032334
2007 Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 150 17700644
2004 The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma. Blood 133 15331441
1999 Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B. British journal of pharmacology 117 10602317
2022 BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis. Frontiers in pharmacology 109 35517783
2008 PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophrenia research 100 18394866
2007 Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology 91 18060387
2012 ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. PloS one 85 22384243
2016 PDE4B as a microglia target to reduce neuroinflammation. Glia 82 27038323
1997 Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase, HSPDE4B3. The Biochemical journal 82 9371714
2020 Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure. Circulation 75 32264695
2008 DISC1, PDE4B, and NDE1 at the centrosome and synapse. Biochemical and biophysical research communications 74 18983980
2007 Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology 73 17333137
2007 The PDE4B gene confers sex-specific protection against schizophrenia. Psychiatric genetics 72 17417055
2018 Following spinal cord injury, PDE4B drives an acute, local inflammatory response and a chronic, systemic response exacerbated by gut dysbiosis and endotoxemia. Neurobiology of disease 67 30557659
2011 Association of PDE4B polymorphisms and schizophrenia in Northwestern Han Chinese. Human genetics 65 22160351
2008 Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease. American journal of physiology. Gastrointestinal and liver physiology 65 18687753
2017 Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System. Scientific reports 63 28054669
2011 Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice. Neuropharmacology 63 21376063
2022 Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils and Microcirculation. Circulation research 52 35899614
2013 Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD. Nature communications 52 23575688
2011 PDE4D and PDE4B function in distinct subcellular compartments in mouse embryonic fibroblasts. The Journal of biological chemistry 51 21288894
2011 Enhanced long-term depression and impaired reversal learning in phosphodiesterase 4B-knockout (PDE4B-/-) mice. Neuropharmacology 47 21458469
2016 Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis. The Journal of pathology 45 27287961
2009 Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode. Bioorganic & medicinal chemistry 45 19525117
2017 Smurf2, an E3 ubiquitin ligase, interacts with PDE4B and attenuates liver fibrosis through miR-132 mediated CTGF inhibition. Biochimica et biophysica acta. Molecular cell research 43 29100790
2022 The regulatory role of PDE4B in the progression of inflammatory function study. Frontiers in pharmacology 42 36278172
2014 Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Bioorganic & medicinal chemistry letters 40 24998378
2008 Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population. Journal of psychiatric research 40 18329668
2021 Long non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) sponges microRNA-124-3p to up-regulate phosphodiesterase 4B (PDE4B) to accelerate the progression of Parkinson's disease. Bioengineered 39 33522352
2015 Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi. Proceedings of the National Academy of Sciences of the United States of America 38 25831493
2022 LncRNA GAS5 Knockdown Mitigates Hepatic Lipid Accumulation via Regulating MiR-26a-5p/PDE4B to Activate cAMP/CREB Pathway. Frontiers in endocrinology 33 35957809
2016 Ferulic acid prevents LPS-induced up-regulation of PDE4B and stimulates the cAMP/CREB signaling pathway in PC12 cells. Acta pharmacologica Sinica 33 27665850
2020 Inhibition of PDE4/PDE4B improves renal function and ameliorates inflammation in cisplatin-induced acute kidney injury. American journal of physiology. Renal physiology 32 31961716
2002 DMSO-treated HL60 cells: a model of neutrophil-like cells mainly expressing PDE4B subtype. International immunopharmacology 31 12469939
1995 Chromosomal localization of the human and rat genes (PDE4D and PDE4B) encoding the cAMP-specific phosphodiesterases 3 and 4. Cytogenetics and cell genetics 31 7835077
2017 Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus. BMC neuroscience 29 29197324
2010 Association study of PDE4B gene variants in Scandinavian schizophrenia and bipolar disorder multicenter case-control samples. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 29 19350560
2024 PDE4B inhibition by nerandomilast: Effects on lung fibrosis and transcriptome in fibrotic rats and on biomarkers in human lung epithelial cells. British journal of pharmacology 28 39183442
2008 Differential distribution of PDE4B splice variant mRNAs in rat brain and the effects of systemic administration of LPS in their expression. Synapse (New York, N.Y.) 28 17960764
2020 Rutaecarpine derivative Cpd-6c alleviates acute kidney injury by targeting PDE4B, a key enzyme mediating inflammation in cisplatin nephropathy. Biochemical pharmacology 27 32622666
2019 InCl3 mediated heteroarylation of indoles and their derivatization via CH activation strategy: Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis. European journal of medicinal chemistry 27 31035240
2011 Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer. The Prostate 27 22529021
2021 Declines in PDE4B activity promote myopia progression through downregulation of scleral collagen expression. Experimental eye research 23 34506801
2013 Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potential PDE4B inhibitors against cancer cells. Bioorganic & medicinal chemistry letters 23 24215890
2023 Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop. Journal of translational medicine 22 36737782
2014 Blockade of PDE4B limits lung vascular permeability and lung inflammation in LPS-induced acute lung injury. Biochemical and biophysical research communications 21 25019986
2021 Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains. International journal of molecular sciences 20 34064099
2013 Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors. Organic & biomolecular chemistry 20 23436140
2021 PDE4B Induces Epithelial-to-Mesenchymal Transition in Bladder Cancer Cells and Is Transcriptionally Suppressed by CBX7. Frontiers in cell and developmental biology 19 34977026
2005 Phosphodiesterase 4B (PDE4B) and cAMP-level regulation within different tissue fractions of rat hippocampal slices during long-term potentiation in vitro. Brain research 19 15829230
2024 Protective effect of PDE4B subtype-specific inhibition in an App knock-in mouse model for Alzheimer's disease. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 18 38521860
2022 MiR-124-3p targeting PDE4B attenuates LPS-induced ALI through the TLR4/NF-κB signaling pathway. International immunopharmacology 18 35063752
2019 Anti‑inflammatory effect of ciclamilast in an allergic model involving the expression of PDE4B. Molecular medicine reports 18 30628641
2018 A Novel Catecholopyrimidine Based Small Molecule PDE4B Inhibitor Suppresses Inflammatory Cytokines in Atopic Mice. Frontiers in pharmacology 18 29867490
2015 Venlafaxine increases cell proliferation and regulates DISC1, PDE4B and NMDA receptor 2B expression in the hippocampus in chronic mild stress mice. European journal of pharmacology 18 25769842
2020 Low concentration of Bupivacaine ameliorates painful diabetic neuropathy by mediating miR-23a/PDE4B axis in microglia. European journal of pharmacology 17 33144067
2018 Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile. European journal of medicinal chemistry 17 29477888
2022 qPCR Analysis Reveals Association of Differential Expression of SRR, NFKB1, and PDE4B Genes With Type 2 Diabetes Mellitus. Frontiers in endocrinology 16 35046895
2021 Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA. Antioxidants (Basel, Switzerland) 16 33809405
2021 Gut probiotic Lactobacillus rhamnosus attenuates PDE4B-mediated interleukin-6 induced by SARS-CoV-2 membrane glycoprotein. The Journal of nutritional biochemistry 16 34271099
2019 Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival. Leukemia 16 31138843
2013 Genome wide mapping reveals PDE4B as an IL-2 induced STAT5 target gene in activated human PBMCs and lymphoid cancer cells. PloS one 15 23451206
2022 Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease. Pharmaceutics 14 36145643
2021 Evidence for reprogramming of monocytes into reparative alveolar macrophages in vivo by targeting PDE4b. American journal of physiology. Lung cellular and molecular physiology 14 34318714
2020 Identification of a Selective PDE4B Inhibitor From Bryophyllum pinnatum by Target Fishing Study and In Vitro Evaluation of Quercetin 3-O-α-L-Arabinopyranosyl-(1→2)-O-α-L-Rhamnopyranoside. Frontiers in pharmacology 14 32038254
2000 Noradrenergic lesions differentially alter the expression of two subtypes of low Km cAMP-sensitive phosphodiesterase type 4 (PDE4A and PDE4B) in rat brain. Brain research 12 10837797
2022 Novel quinoline-based derivatives: A new class of PDE4B inhibitors for adjuvant-induced arthritis. European journal of medicinal chemistry 11 35660249
2021 Discovery of polymethoxyflavones as potential cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and phosphodiesterase 4B (PDE4B) inhibitors. Journal of receptor and signal transduction research 11 34323638
2024 Anti-Inflammatory Effects of miR-369-3p via PDE4B in Intestinal Inflammatory Response. International journal of molecular sciences 10 39126032
2018 Tetrahydroquinoline and tetrahydroisoquinoline derivatives as potential selective PDE4B inhibitors. Bioorganic & medicinal chemistry letters 10 30131242
2014 Synthesis of 2H-1,3-benzoxazin-4(3H)-one derivatives containing indole moiety: their in vitro evaluation against PDE4B. Bioorganic & medicinal chemistry letters 10 24440301
2008 Minimizing a QTL region for intramuscular fat content by characterizing the porcine Phosphodiesterase 4B (PDE4B) gene. BMB reports 10 18593531
2024 Nobiletin, as a Novel PDE4B Inhibitor, Alleviates Asthma Symptoms by Activating the cAMP-PKA-CREB Signaling Pathway. International journal of molecular sciences 9 39408735
2023 Selective PDE4B and PDE4D inhibitors produce distinct behavioral responses to ethanol and GABAergic drugs in mice. Neuropharmacology 9 36935006
2022 PDE4B Proposed as a High Myopia Susceptibility Gene in Chinese Population. Frontiers in genetics 9 35116054
2022 PDE4B Is a Homeostatic Regulator of Cyclic AMP in Dendritic Cells. Frontiers in pharmacology 9 35387344
2025 Microglial circDlg1 modulates neuroinflammation by blocking PDE4B ubiquitination-dependent degradation associated with Alzheimer's disease. Theranostics 8 40093898
2010 Association study of PDE4B with panic disorder in the Japanese population. Progress in neuro-psychopharmacology & biological psychiatry 8 21184794
2022 Population genetics of PDE4B (phosphodiesterase-4B) in neglected Native Americans: Implications for cancer pharmacogenetics. Clinical and translational science 7 35266293
2025 PDE4B promotes ferroptosis in nucleus pulposus cells and is involved in intervertebral disc degeneration. Scientific reports 6 39893206
2024 Rationale design and synthesis of new roflumilast analogues as preferential selective and potent PDE-4B inhibitors. Bioorganic chemistry 6 39467506
2017 Depletion of D3 dopamine receptor affects methamphetamine-induced expression patterns of Pde4b and Atf3. Neuroscience letters 6 29175029
2015 Design, synthesis and biological evaluation of novel quinazoline-based anti-inflammatory agents acting as PDE4B inhibitors. Chemical & pharmaceutical bulletin 6 25748781
2025 Shenghui decoction inhibits neuronal cell apoptosis to improve Alzheimer's disease through the PDE4B/cAMP/CREB signaling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 5 39787692
2024 Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice. Cells 5 38920631
2025 Nerandomilast, a PDE4B inhibitor, alleviates silica-induced lung inflammation and fibrosis by inhibition of NLRP3 inflammasome and TGF-β/Smad signalling. British journal of pharmacology 4 41255094
2024 Zoledronic Acid Accelerates ER Stress-Mediated Inflammation by Increasing PDE4B Expression in Bisphosphonate-Related Osteonecrosis of the Jaw. Applied biochemistry and biotechnology 4 38523176
2024 PDE4B Missense Variant Increases Susceptibility to Post-traumatic Stress Disorder-Relevant Phenotypes in Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 4 39256048
2024 COF-SO3H-Catalyzed Synthesis of Pyrazoline-Pyridine Hybrids with Dual Antioxidant and Anti-Inflammatory Activity Targeting PDE4B. Chemistry & biodiversity 4 39523465
2019 Exploring the Role of Water Molecules in the Ligand Binding Domain of PDE4B and PDE4D: Virtual Screening Based Molecular Docking of Some Active Scaffolds. Current computer-aided drug design 4 30394213
2019 PDE4B gene polymorphism in Russian patients with panic disorder. AIMS genetics 4 31663033
2018 Dexamethasone Inhibits Synergistic Induction of PDE4B Expression by Roflumilast and Bacterium NTHi. International journal of molecular sciences 4 30413022
2015 Association analysis of PDE4B polymorphisms with schizophrenia and smooth pursuit eye movement abnormality in a Korean population. General physiology and biophysics 4 25926551
2015 Synthesis of New Congeners of 1-methyl-3-aminoisoquinolines, Evaluation of Their Cytotoxic Activity, In Silico and In Vitro Study of Their Molecular Targets as PDE4B. Chemical biology & drug design 4 26613238
2025 Pde4b-regulated cAMP signaling pathway in the AUDGABA-S1TrSst circuit underlies acute-stress-induced anxiety-like behavior. Cell reports 3 39891910
2025 PDE4B Inhibition: Exploring the Landscape of Chemistry Behind Specific PDE4B Inhibitors, Drug Design, and Discovery. Archiv der Pharmazie 3 40654275
2025 Jascayd (nerandomilast): a novel PDE4B inhibitor for idiopathic pulmonary fibrosis. Annals of medicine and surgery (2012) 3 41497055
2022 Transcription factor JDP2 activates PDE4B to participate in hypoxia/reoxygenation-induced H9c2 cell injury. Experimental and therapeutic medicine 3 35401806

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