Affinage

PDE10A

cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A · UniProt Q9Y233

Length
1055 aa
Mass
114.9 kDa
Annotated
2026-04-29
100 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDE10A is a dual-substrate cyclic nucleotide phosphodiesterase that hydrolyzes both cAMP (Km ~0.05–0.26 µM) and cGMP (Km ~3–7 µM), with cross-substrate inhibition, and contains two N-terminal GAF domains—GAF-B serving as an allosteric activator of the C-terminal catalytic domain upon cAMP binding—and is predominantly localized to postsynaptic membranes of striatal medium spiny neurons in both direct (D1) and indirect (D2) pathways (PMID:10373451, PMID:10359840, PMID:16483723, PMID:27058447). By controlling cAMP/PKA signaling in these neurons, PDE10A regulates DARPP-32 phosphorylation, CREB-dependent transcription, and the integration of dopaminergic and glutamatergic inputs, with PKA-dependent responses selectively amplified in D2 medium spiny neurons through a DARPP-32/protein phosphatase-1 feedback loop (PMID:18923023, PMID:26465004, PMID:19765598). De novo mutations in GAF-B cause childhood-onset chorea by disrupting allosteric activation, while recessive GAF-A mutations cause loss of PDE10A through impaired membrane trafficking and cytosolic degradation (PMID:27058447, PMID:31871190). Beyond the striatum, PDE10A regulates cGMP/PKG-dependent cardiomyocyte survival, CNP/NPR2/cGMP/PKGIα-dependent vascular smooth muscle cell proliferation, and adipocyte thermogenesis (PMID:37232184, PMID:34550322, PMID:27247380).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1999 High

    The fundamental enzymatic identity of PDE10A was established as a dual-substrate phosphodiesterase with much higher affinity for cAMP than cGMP and cross-substrate inhibition, resolving that this new PDE family member could simultaneously regulate both cyclic nucleotide pools.

    Evidence Recombinant expression in COS-7 cells and yeast with kinetic characterization by three independent laboratories

    PMID:10359840 PMID:10373451 PMID:10393245

    Open questions at the time
    • No cellular context for substrate preference in vivo
    • Allosteric regulation by GAF domains not yet characterized
    • No information on post-translational regulation
  2. 2004 High

    The discovery that PDE10A is highly and selectively expressed in striatal medium spiny neurons—localized to postsynaptic membranes in dendrites and spines but excluded from interneurons—defined the cellular compartment where PDE10A exerts its primary function.

    Evidence Immunohistochemistry, confocal microscopy, subcellular fractionation, and immuno-electron microscopy in rat and primate striatum

    PMID:12967715 PMID:16483723

    Open questions at the time
    • Mechanism of membrane targeting not defined
    • Whether localization differs between D1 and D2 MSNs unknown
    • Functional significance of axonal transport to globus pallidus/substantia nigra terminals unresolved
  3. 2008 High

    PDE10A was positioned as a postsynaptic integrator of dopaminergic signaling in striatum: its inhibition activated cAMP/PKA signaling in both D1 and D2 MSNs, potentiating D1 and opposing D2 receptor effects through DARPP-32 phosphorylation, and drove expression of output pathway markers (substance P, enkephalin) via cAMP rather than cGMP.

    Evidence In vivo and in vitro pharmacology with selective PDE inhibitors in mouse striatum, phosphoprotein analysis, and genetic epistasis with nNOS-knockout mice

    PMID:18923023 PMID:19765598

    Open questions at the time
    • Whether cGMP signaling contributes in specific physiological contexts still unclear
    • Downstream transcriptional targets beyond cfos/substance P/enkephalin not mapped
    • Role in synaptic plasticity not directly tested
  4. 2010 Medium

    PDE10A inhibition in a Huntington's disease model increased CREB phosphorylation and BDNF levels in striatum, linking PDE10A's cAMP-degrading activity to CREB-mediated neuroprotective transcription in medium spiny neurons.

    Evidence In vivo pharmacological treatment of R6/2 HD mice with TP-10, immunohistochemistry, and behavioral assays

    PMID:20976216

    Open questions at the time
    • Single pharmacological agent without genetic confirmation
    • Whether BDNF induction is cell-autonomous in MSNs not established
    • Long-term therapeutic efficacy unclear
  5. 2015 High

    Live biosensor imaging resolved the paradox of uniform cAMP elevation but selective PKA activation: PDE10A inhibition raised cAMP equally in D1 and D2 MSNs, but PKA-dependent signaling was selectively amplified in D2 MSNs via DARPP-32-mediated inhibition of protein phosphatase-1, establishing a cell-type-specific signal amplification mechanism.

    Evidence FRET-based cAMP/PKA/cGMP biosensors in mouse brain slices combined with DARPP-32 phosphosite-mutant mice

    PMID:26465004

    Open questions at the time
    • Whether this selectivity holds during physiological (non-pharmacological) fluctuations in PDE10A activity unknown
    • Identity of the phosphatase complexes differentially regulated in D1 vs D2 MSNs not defined
  6. 2016 High

    Human genetic and biochemical studies established that the GAF-B domain functions as an allosteric activator of the catalytic domain upon cAMP binding: de novo GAF-B mutations causing childhood-onset chorea abolished this allosteric stimulation without affecting basal catalytic activity, directly linking GAF-B-mediated regulation to human disease.

    Evidence Whole-exome sequencing, recombinant mutant enzyme kinetics, and structural modeling

    PMID:27058447

    Open questions at the time
    • Crystal structure of full-length PDE10A including GAF domains not available
    • How loss of allosteric activation leads to chorea at the circuit level not established
  7. 2016 High

    Functional roles for PDE10A outside the brain were established: in colon cancer cells PDE10A inhibition activated PKG to suppress β-catenin signaling and induce apoptosis, and in brown/beige adipocytes PDE10A inhibition stimulated thermogenic gene expression, demonstrating tissue-specific engagement of cGMP and cAMP effector pathways.

    Evidence Pharmacological inhibition and shRNA knockdown in cancer cell lines; PET imaging and MP-10 treatment in mouse adipose tissue and human adipocyte cultures

    PMID:26713600 PMID:27247380

    Open questions at the time
    • Relative contribution of cAMP vs cGMP in adipocyte thermogenesis not dissected
    • Whether PDE10A is a viable therapeutic target in cancer requires independent validation
  8. 2019 High

    Domain-specific disease mechanisms were delineated: recessive GAF-A mutations cause PDE10A loss through impaired membrane trafficking and cytosolic degradation, while dominant GAF-B mutations cause protein misfolding—two distinct pathological mechanisms converging on PDE10A dysfunction.

    Evidence Cell-based trafficking, protein stability/degradation assays, immunofluorescence, and biochemical fractionation

    PMID:31871190

    Open questions at the time
    • In vivo confirmation of trafficking defect in patient-derived neurons lacking
    • Whether correcting trafficking rescues function not tested
    • Ubiquitin-proteasome vs autophagy pathway for degradation not distinguished
  9. 2022 High

    PDE10A was identified as a critical regulator of vascular smooth muscle cell proliferation through the CNP/NPR2/cGMP/PKGIα axis, with PDE10A deficiency or inhibition arresting cell cycle at G1 and reducing injury-induced neointimal thickening by ≥50%.

    Evidence PDE10A knockout mice and pharmacological inhibition with cell cycle analysis and femoral artery wire injury model

    PMID:34550322

    Open questions at the time
    • Whether PDE10A also regulates cAMP-dependent proliferative signaling in SMCs not addressed
    • Contribution of PDE10A relative to other PDEs in vascular SMCs not quantified
  10. 2025 Medium

    A post-translational degradation pathway for PDE10A was identified: the E3 ubiquitin ligase RNF220 directly ubiquitinates PDE10A via K48-linked chains for proteasomal degradation, regulated upstream by METTL3-mediated m6A modification of RNF220 mRNA.

    Evidence Co-immunoprecipitation, ubiquitination assays, CRISPR knockout in bladder cancer cells

    PMID:40158470

    Open questions at the time
    • Interaction awaits independent replication
    • Whether RNF220-mediated degradation of PDE10A operates in striatal neurons not tested
    • Structural basis of RNF220-PDE10A interaction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structure of PDE10A including GAF domains in active and inactive conformations, the mechanisms determining isoform-specific membrane targeting, and the relative physiological contributions of cAMP versus cGMP hydrolysis in different tissue contexts remain unresolved.
  • No full-length crystal or cryo-EM structure available
  • Isoform-specific trafficking mechanism (PDE10A2 membrane vs PDE10A1 cytosol) not molecularly defined
  • In vivo substrate selectivity (cAMP vs cGMP) in non-neuronal tissues not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0009975 cyclase activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CREBDARPP-32PKGIΑRNF220

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PDE10A is a dual-substrate phosphodiesterase that hydrolyzes both cAMP and cGMP; recombinant PDE10A expressed in COS-7 cells showed Km values of 0.26 µM for cAMP and 7.2 µM for cGMP, with Vmax for cGMP approximately twice that for cAMP. cGMP inhibited cAMP hydrolysis and cAMP inhibited cGMP hydrolysis, indicating cross-substrate inhibition. The N-terminal portion contains a putative cGMP-binding (GAF) domain and the C-terminal region encodes the catalytic domain. Recombinant expression in COS-7 cells, enzyme kinetics assay, inhibitor profiling The Journal of biological chemistry High 10373451
1999 Mouse PDE10A contains two N-terminal GAF domains (homologous to PDE2, PDE5, PDE6) that likely constitute a low-affinity cGMP-binding site, and a C-terminal catalytic domain. The enzyme hydrolyzes cAMP with Km of 0.05 µM and cGMP with Km of 3 µM, with Vmax ratio (cGMP/cAMP) of 4.7. cDNA cloning, sequence analysis, recombinant expression, enzyme kinetics Proceedings of the National Academy of Sciences of the United States of America High 10359840
1999 PDE10A hydrolyzes both cAMP and cGMP; recombinant protein expressed in yeast was enzymatically active. Two splice variants (PDE10A1 and PDE10A2) share 766 common amino acids including GAF-like domains and the catalytic domain. Recombinant expression in yeast, enzyme activity assay, Northern analysis Gene High 10393245
2003 PDE10A protein is highly expressed in the cell bodies of striatal medium spiny neurons (caudate nucleus, nucleus accumbens, olfactory tubercle) and is transported throughout the dendritic tree and down axons to terminals in globus pallidus and substantia nigra, indicating axonal transport of the enzyme. Outside the striatum, immunoreactivity is restricted to cell bodies, suggesting a distinct subcellular function in these regions. Immunohistochemistry with monoclonal antibody (24F3.F11), Western blot, in situ hybridization in rat brain Brain research High 12967715
2006 PDE10A is exclusively expressed in medium spiny neurons of the striatum (excluded from all classes of interneurons), is primarily membrane-bound, and is localized to postsynaptic membranes in dendrites and spines of medium spiny neurons. Subcellular fractionation and immuno-electron microscopy showed PDE10A is present in the synaptosomal fraction, associated with membranes at the edge of the postsynaptic density but not within it. Confocal microscopy, subcellular fractionation, immuno-electron microscopy in rat and cynomolgus monkey striatum Neuroscience High 16483723
2008 PDE10A inhibition (via papaverine) activates cAMP/PKA signaling in both striatonigral and striatopallidal medium spiny neurons, resulting in potentiation of dopamine D1 receptor signaling (increased DARPP-32 Thr34 and GluR1 Ser845 phosphorylation) and inhibition of dopamine D2 receptor signaling, without affecting presynaptic dopaminergic terminals (no effect on tyrosine hydroxylase phosphorylation or dopamine turnover). PDE4 inhibition by contrast acts presynaptically. In vitro and in vivo biochemical assays in mouse striatum, selective PDE inhibitor pharmacology, phosphoprotein analysis The Journal of neuroscience High 18923023
2009 PDE10A inhibition controls striatal gene expression by regulating cAMP (but not cGMP) signaling in medium spiny neurons; PDE10A inhibitors increase cfos, substance P (direct pathway marker), and enkephalin (indirect pathway marker) mRNA, indicating PDE10A modulates both striatal output pathways. The cAMP-dependence was confirmed by absence of cGMP elevation in nNOS-deficient mice not affecting cfos induction. In vivo pharmacology in rats and nNOS-knockout mice, quantitative RT-PCR for mRNA Neuropharmacology High 19765598
2004 Specific PDE10A splice variants (Pde10A3) are upregulated following long-term potentiation induction in rat hippocampus. In transfected Cos7 cells, Pde10A3 reduces atrial natriuretic peptide-induced elevation in cGMP levels without affecting basal cGMP levels, suggesting PDE10A splice variants modulate cGMP signaling in a stimulus-dependent manner. Differential display, in situ hybridization, RT-PCR, transient transfection in Cos7 cells, cGMP assay The Journal of biological chemistry Medium 14752115
2016 De novo heterozygous mutations in the GAF-B domain of PDE10A (p.Phe300Leu and p.Phe334Leu) cause childhood-onset chorea. In vitro functional studies showed these mutations do not affect basal PDE10A catalytic activity but severely disrupt the stimulatory effect of cAMP binding to the GAF-B domain, which normally allosterically stimulates the catalytic domain. In silico modeling showed the substituted residues are located deep in the cAMP binding pocket of GAF-B. In vitro functional assay of recombinant mutant proteins, in silico structural modeling, whole-exome sequencing American journal of human genetics High 27058447
2019 Recessive PDE10A mutations in the GAF-A domain cause loss of striatal PDE10A protein due to irregular intracellular trafficking and increased degradation in the cytosolic compartment. Dominant mutations in the GAF-B domain cause PDE10A misfolding. Thus, different disease-causing mutations impair PDE10A through distinct mechanisms: GAF-A mutations impair membrane compartmentalization/trafficking, while GAF-B mutations cause misfolding. Cell-based trafficking assays, protein stability/degradation assays, immunofluorescence, biochemical fractionation Proceedings of the National Academy of Sciences of the United States of America High 31871190
2015 PDE10A inhibition in striatal slices produces a steady-state increase in intracellular cAMP in both D1 (direct pathway) and D2 (indirect pathway) medium spiny neurons, but the downstream PKA-dependent (AKAR3 phosphorylation) signal is strong selectively in D2 MSNs. This selectivity depends on DARPP-32 phosphorylation at the PKA-regulated site, which inhibits protein phosphatase-1 more effectively in D2 MSNs than D1 MSNs. FRET-based biosensors for cAMP, PKA, and cGMP in mouse brain slices; in vivo immunohistochemistry; genetic mouse models with DARPP-32 phosphorylation-site mutations eNeuro High 26465004
2009 Crystal structure of human PDE10A catalytic domain in complex with papaverine was solved to 2.8 Å resolution using glutaraldehyde cross-linked crystals, revealing the binding mode of papaverine in the catalytic domain. X-ray crystallography of cross-linked protein crystals soaked with papaverine Acta crystallographica. Section D, Biological crystallography High 19622871
2023 PDE10A contributes to doxorubicin-induced cardiomyocyte death by increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage via antagonizing cGMP/PKG signaling. PDE10A also promotes cardiomyocyte atrophy by potentiating FoxO3 signaling through both cAMP/PKA- and cGMP/PKG-dependent pathways. PDE10A deficiency or inhibition with TP-10 alleviated these effects in isolated cardiomyocytes and in vivo. PDE10A global KO mice, pharmacological inhibition (TP-10), RNA sequencing, in vitro cardiomyocyte assays, mechanistic pathway analysis Circulation research High 37232184
2016 PDE10A inhibition (Pf-2545920/MP-10) increases cGMP and cAMP levels in colon tumor cells, activates PKG and PKA, inhibits β-catenin nuclear translocation, reduces β-catenin-mediated transcription of survivin, and induces caspase activation and apoptosis selectively in cancer cells. PDE10A knockdown by shRNA reduces the sensitivity to Pf-2545920. siRNA/shRNA knockdown, pharmacological inhibition, cGMP/cAMP measurement, β-catenin nuclear translocation assay, caspase activation assay Oncotarget High 26713600
2022 PDE10A deficiency or inhibition arrests vascular smooth muscle cell (SMC) cell cycle at G1-phase with reduction of cyclin D1. The anti-mitotic effect of PDE10A inhibition is dependent on cGMP-dependent protein kinase Iα (PKGIα), involving C-natriuretic peptide (CNP) and particulate guanylate cyclase receptor NPR2. Both PDE10A KO and inhibition decreased injury-induced intimal thickening in a mouse femoral artery wire injury model by at least 50%. PDE10A KO mice, pharmacological inhibition, cell cycle analysis (flow cytometry), BrdU incorporation, in vivo vascular injury model Cardiovascular research High 34550322
2016 PDE10A is expressed in brown adipose tissue of mice and in human supraclavicular brown/beige adipocytes. Pharmacological inactivation of PDE10A with MP-10 stimulated thermogenic gene expression in human brown adipocytes, induced browning of human white adipocytes, and recruited BAT/potentiated thermogenesis in vivo, revealing a thermoregulatory role for PDE10A in adipocytes. Small-animal PET/MRI with [(18)F]-AQ28A radioligand, pharmacological inhibition with MP-10 in mice and human adipocyte cultures, thermogenic gene expression assays EMBO molecular medicine High 27247380
2018 miR-137 targets Pde10a mRNA; partial loss of miR-137 in heterozygous cKO mice elevates PDE10A protein levels in brain and causes synaptic plasticity deficits, repetitive behavior, and impaired learning and social behavior. Treatment with the PDE10A inhibitor papaverine or Pde10a knockdown rescues these behavioral deficits, establishing PDE10A as a downstream effector of miR-137. miR-137 conditional KO mice, transcriptomic and proteomic analysis, pharmacological rescue with papaverine, Pde10a shRNA knockdown Nature neuroscience High 30397325
2016 PDE10A isoforms differ in subcellular trafficking: PDE10A2 is found predominantly at the plasma membrane while PDE10A1 and PDE10A19 remain primarily in the cytosol, suggesting N-terminal isoform differences regulate subcellular localization. RNA-sequencing, 5' RLM-RACE of human putamen and caudate nucleus, isoform analysis Gene Medium 28042091
2016 PDE10A activity in vascular smooth muscle cells and in spermatozoa: PDE10A is detected as the major cAMP-hydrolyzing enzyme in human spermatozoa (major cAMP-PDE activity is papaverine-sensitive), confirmed by Western blot, immunoprecipitation, and mass spectrometry. Enzyme activity assay with selective inhibitors, subcellular fractionation, Western blot, immunoprecipitation, mass spectrometry Biochimica et biophysica acta. General subjects Medium 27836756
2011 PDE10A inhibition with papaverine activates ERK phosphorylation in both D1- and D2-enriched striatal neurons in male rats. This effect is absent in female rats due to estrogen regulation of D2 receptor levels; ovariectomy restores papaverine-induced ERK phosphorylation to male levels. Thus, sex hormones modulate PDE10A-dependent signaling through D2 receptor expression. Acute rat striatal slices, immunoblotting for phospho-ERK1/2, dopamine receptor agonist/antagonist pharmacology, ovariectomy model Neuropharmacology Medium 21816164
2025 The E3 ubiquitin ligase RNF220 directly interacts with PDE10A and facilitates its K48-linked ubiquitination and proteasomal degradation in cisplatin-resistant bladder cancer cells. METTL3-mediated m6A modification stabilizes RNF220 mRNA in an IGF2BP2-dependent manner, leading to increased RNF220 expression and PDE10A degradation. RNF220-mediated PDE10A destabilization also promotes PD-L1 expression facilitating immune evasion. Co-immunoprecipitation, ubiquitination assay, CRISPR/Cas9 KO, proteomic analysis, in vitro and in vivo functional assays Biochemical pharmacology Medium 40158470
2020 PDE10A inhibition (MP-10) suppresses microglial activation by inhibiting phosphorylation of c-Jun N-terminal kinase and Akt, reducing NF-κB/AP-1 activity, and upregulating Nrf2/ARE and PKA/CREB signaling pathways in LPS-stimulated BV2 microglial cells. In MPTP-induced Parkinson's disease mice, MP-10 rescued behavioral deficits and dopaminergic neuronal death and reduced microglial activation. LPS-stimulated BV2 cell model, Western blot/RT-PCR for signaling pathway components, in vivo MPTP mouse model Journal of neuroimmune pharmacology Medium 32671618
2022 CXCR2 inhibition promotes oligodendrocyte precursor cell (OPC) differentiation and remyelination by downregulating PDE10A expression downstream of CXCR2. PDE10A inhibition mimics CXCR2 inhibition in promoting OPC differentiation; overexpression of PDE10A suppresses OPC differentiation. The mechanism involves PDE10A/cAMP/ERK1/2 signaling activating transcription factors SOX10, OLIG2, MYRF, and ZFP24. Primary OPC culture, CXCR2 inhibitor and PDE10A inhibitor/overexpression, immunofluorescence, Western blot, in vivo ethidium bromide demyelination model Neurobiology of disease Medium 36603746
2010 PDE10A inhibition in R6/2 Huntington's disease mice increases striatal and cortical levels of phosphorylated CREB and BDNF, reduces neuronal intranuclear inclusion formation, and alleviates neurological deficits, supporting PDE10A's role in regulating CREB/cAMP transcriptional signaling in medium spiny neurons. In vivo pharmacological treatment of R6/2 transgenic HD mice with TP-10, immunohistochemistry, behavioral assays, Western blot PloS one Medium 20976216

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). The Journal of biological chemistry 337 10373451
1999 Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A. Proceedings of the National Academy of Sciences of the United States of America 326 10359840
2003 Immunohistochemical localization of PDE10A in the rat brain. Brain research 287 12967715
2008 Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. The Journal of neuroscience : the official journal of the Society for Neuroscience 234 18923023
1999 Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide phosphodiesterase. Gene 184 10393245
2005 PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats. The European journal of neuroscience 175 15787711
2006 Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase. Neuroscience 171 16483723
2010 Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease. PloS one 153 20976216
2018 Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. Nature neuroscience 120 30397325
2011 PDE10A inhibitors: novel therapeutic drugs for schizophrenia. Current pharmaceutical design 105 21355834
2016 De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions. American journal of human genetics 93 27058447
2015 Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease. Brain : a journal of neurology 89 26198591
2013 PET imaging shows loss of striatal PDE10A in patients with Huntington disease. Neurology 60 24353339
2014 In vivo assessment and dosimetry of 2 novel PDE10A PET radiotracers in humans: 18F-MNI-659 and 18F-MNI-654. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 55 24898025
2023 PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth. Circulation research 52 37232184
2007 Behavioral characterization of mice deficient in the phosphodiesterase-10A (PDE10A) enzyme on a C57/Bl6N congenic background. Neuropharmacology 52 18061215
2015 Emerging biology of PDE10A. Current pharmaceutical design 51 25159072
2016 β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget 50 26713600
2016 TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 47 26849714
2011 PDE10A and PDE10A-dependent cAMP catabolism are dysregulated oppositely in striatum and nucleus accumbens after lesion of midbrain dopamine neurons in rat: a key step in parkinsonism physiopathology. Neurobiology of disease 46 21515371
2016 A novel thermoregulatory role for PDE10A in mouse and human adipocytes. EMBO molecular medicine 42 27247380
2009 Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A. Neuropharmacology 42 19765598
2010 Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation. Nuclear medicine and biology 41 20447563
2012 Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease. Neurobiology of disease 39 23220622
2012 Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors. Bioorganic & medicinal chemistry letters 38 22365755
2021 PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action? Frontiers in neuroscience 37 33551724
2015 Selective Effects of PDE10A Inhibitors on Striatopallidal Neurons Require Phosphatase Inhibition by DARPP-32. eNeuro 37 26465004
2011 Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors. Bioorganic & medicinal chemistry letters 37 21602043
2000 The human phosphodiesterase PDE10A gene genomic organization and evolutionary relatedness with other PDEs containing GAF domains. European journal of biochemistry 37 10998054
2004 Differential amplification of intron-containing transcripts reveals long term potentiation-associated up-regulation of specific Pde10A phosphodiesterase splice variants. The Journal of biological chemistry 36 14752115
2013 Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A). Journal of medicinal chemistry 35 24102193
2014 Pharmacology of JNJ-42314415, a centrally active phosphodiesterase 10A (PDE10A) inhibitor: a comparison of PDE10A inhibitors with D2 receptor blockers as potential antipsychotic drugs. The Journal of pharmacology and experimental therapeutics 32 24421319
2018 PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology. Movement disorders : official journal of the Movement Disorder Society 30 30345538
2007 PDE-10A inhibitors as insulin secretagogues. Bioorganic & medicinal chemistry letters 29 17400452
2011 Effect of PDE10A inhibitors on MK-801-induced immobility in the forced swim test. Psychopharmacology 27 22147257
2020 Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease. Cellular signalling 26 32119913
2020 The Potent PDE10A Inhibitor MP-10 (PF-2545920) Suppresses Microglial Activation in LPS-Induced Neuroinflammation and MPTP-Induced Parkinson's Disease Mouse Models. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 24 32671618
2017 In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects. Neuropharmacology 24 28122201
2012 Discovery of selective biaryl ethers as PDE10A inhibitors: improvement in potency and mitigation of Pgp-mediated efflux. Bioorganic & medicinal chemistry letters 24 23149228
2012 Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer. Journal of medicinal chemistry 23 22548439
2009 Cross-linking of protein crystals as an aid in the generation of binary protein-ligand crystal complexes, exemplified by the human PDE10a-papaverine structure. Acta crystallographica. Section D, Biological crystallography 22 19622871
2017 Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a. Psychopharmacology 21 28337525
2011 The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices. Neuropharmacology 21 21816164
2019 Advances in Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 1: Overview of the Chemical and Biological Research. Current drug targets 20 30091414
2014 Initial characterization of a PDE10A selective positron emission tomography tracer [11C]AMG 7980 in non-human primates. Nuclear medicine and biology 20 24607437
2010 Impaired appetitively as well as aversively motivated behaviors and learning in PDE10A-deficient mice suggest a role for striatal signaling in evaluative salience attribution. Neurobiology of learning and memory 20 21130175
2018 TAK-063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia. CNS neuroscience & therapeutics 19 29318783
2014 Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal. Frontiers in integrative neuroscience 19 24782725
2013 N-Methylanilide and N-methylbenzamide derivatives as phosphodiesterase 10A (PDE10A) inhibitors. Bioorganic & medicinal chemistry 19 23978358
2014 PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways. Pharmacology research & perspectives 18 25505601
2018 Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors. Chemical & pharmaceutical bulletin 17 29491261
2017 Insight into the structural requirements of pyrimidine-based phosphodiesterase 10A (PDE10A) inhibitors by multiple validated 3D QSAR approaches. SAR and QSAR in environmental research 17 28322591
2016 Cyclic nucleotide phosphodiesterases in human spermatozoa and seminal fluid: Presence of an active PDE10A in human spermatozoa. Biochimica et biophysica acta. General subjects 17 27836756
2014 Genetic deletion of PDE10A selectively impairs incentive salience attribution and decreases medium spiny neuron excitability. Behavioural brain research 17 24698799
2022 Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer. Journal of ovarian research 16 36324187
2021 Medicinal chemistry strategies for the development of phosphodiesterase 10A (PDE10A) inhibitors - An update of recent progress. European journal of medicinal chemistry 16 33581555
2020 PDE10A Inhibition Reduces the Manifestation of Pathology in DMD Zebrafish and Represses the Genetic Modifier PITPNA. Molecular therapy : the journal of the American Society of Gene Therapy 16 33221436
2015 Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy. Neuropharmacology 16 26522433
2016 Novel PDE10A transcript diversity in the human striatum: Insights into gene complexity, conservation and regulation. Gene 15 28042091
2013 Identification and optimization of PDE10A inhibitors using fragment-based screening by nanocalorimetry and X-ray crystallography. Journal of biomolecular screening 15 24375910
2024 Effects of PDE10A inhibitor MK-8189 in people with an acute episode of schizophrenia: A randomized proof-of-concept clinical trial. Schizophrenia research 14 38851166
2022 Role of PDE10A in vascular smooth muscle cell hyperplasia and pathological vascular remodelling. Cardiovascular research 14 34550322
2014 Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A). ACS medicinal chemistry letters 14 24944747
2017 Familial choreoathetosis due to novel heterozygous mutation in PDE10A. American journal of medical genetics. Part A 13 29130591
2016 Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats. PloS one 13 26808689
2020 Balanced Activation of Striatal Output Pathways by Faster Off-Rate PDE10A Inhibitors Elicits Not Only Antipsychotic-Like Effects But Also Procognitive Effects in Rodents. The international journal of neuropsychopharmacology 12 31689714
2019 Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme. Proceedings of the National Academy of Sciences of the United States of America 12 31871190
2009 PDE9A, PDE10A, and PDE11A expression in rat trigeminovascular pain signalling system. Brain research 12 19445908
2018 Combined treatment with a selective PDE10A inhibitor TAK-063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic-like effects without affecting plasma prolactin levels and cataleptic responses in rodents. Pharmacology research & perspectives 11 29417763
2018 Synthesis and characterization of novel classes of PDE10A inhibitors - 1H-1,3-benzodiazoles and imidazo[1,2-a]pyrimidines. European journal of medicinal chemistry 11 29870883
2022 Inhibition of PDE10A-Rescued TBI-Induced Neuroinflammation and Apoptosis through the cAMP/PKA/NLRP3 Pathway. Evidence-based complementary and alternative medicine : eCAM 10 35463083
2018 PET Radioligands for imaging of the PDE10A in human: current status. Neuroscience letters 10 30099081
2016 Radiosynthesis and biological evaluation of the new PDE10A radioligand [18 F]AQ28A. Journal of labelled compounds & radiopharmaceuticals 10 27896836
2015 Molecular Imaging of PDE10A Knockout Mice with a Novel PET Radiotracer: [(11)C]T-773. Molecular imaging and biology 10 25622810
2017 Pharmacological tools based on imidazole scaffold proved the utility of PDE10A inhibitors for Parkinson's disease. Future medicinal chemistry 9 28485668
2017 Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases. Journal of cheminformatics 9 29290010
2015 Radiosynthesis and initial characterization of a PDE10A specific PET tracer [18F]AMG 580 in non-human primates. Nuclear medicine and biology 9 25935386
2014 Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility. Bioorganic & medicinal chemistry 9 25456383
2019 Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety. Bioorganic & medicinal chemistry 8 31235264
2018 In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains. ACS chemical neuroscience 8 29400443
2015 Development of a series of novel carbon-11 labeled PDE10A inhibitors. Journal of labelled compounds & radiopharmaceuticals 8 25891816
2008 Development of a cell-based assay for screening of phosphodiesterase 10A (PDE10A) inhibitors using a stable recombinant HEK-293 cell line expressing high levels of PDE10A. Biotechnology and applied biochemistry 8 17640173
2021 Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 7 34120511
2020 Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives. Molecules (Basel, Switzerland) 7 32854402
2019 PDE10A mutations help to unwrap the neurobiology of hyperkinetic disorders. Cellular signalling 7 30951862
2017 Development of two fluorine-18 labeled PET radioligands targeting PDE10A and in vivo PET evaluation in nonhuman primates. Nuclear medicine and biology 7 29223715
2022 A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects. Frontiers in pharmacology 6 36438799
2017 Design and optimization of purine derivatives as in vivo active PDE10A inhibitors. Bioorganic & medicinal chemistry 6 28462841
2017 Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits: a Genetics of Diabetes Audit and Research Tayside study (GoDARTS). Pharmacogenetics and genomics 6 28727628
2014 Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part I. Bioorganic & medicinal chemistry letters 6 24725435
2025 N6-methyladenosine-modified RNF220 induces cisplatin resistance and immune escape via regulating PDE10A K48-linked ubiquitination in bladder cancer. Biochemical pharmacology 5 40158470
2014 Structural findings of cinnolines as anti-schizophrenic PDE10A inhibitors through comparative chemometric modeling. Molecular diversity 5 24789056
2024 A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders. Cells 4 39056811
2023 Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway. Neurobiology of disease 4 36603746
2023 Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders. Parkinsonism & related disorders 4 36805523
2022 An insight into reactivity and bioactivity properties of quorum sensing peptides against PDE10A: a computational peptidology approach. Journal of molecular modeling 4 35789297
2021 Structure-based identification of dual ligands at the A2AR and PDE10A with anti-proliferative effects in lung cancer cell-lines. Journal of cheminformatics 4 33658076
2019 In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659. Brain research 4 30664847
2013 Inhibition mechanism exploration of quinoline derivatives as PDE10A inhibitors by in silico analysis. Molecular bioSystems 4 23354020
2016 Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies. ACS medicinal chemistry letters 3 27437084