| 1998 |
PDE9A encodes a cGMP-specific phosphodiesterase with a Km of 170 nM for cGMP (one of the highest affinities among known PDEs) and ~230 µM for cAMP, with Vmax ~4.9 nmol/min/µg; the enzyme is insensitive to classic PDE inhibitors (rolipram, IBMX, dipyridamole) but inhibited by zaprinast (IC50 ~35 µM); activity is approximately twice as high in 1–10 mM Mn²⁺ as in Mg²⁺ or Ca²⁺; PDE9A lacks allosteric cGMP-binding regulatory regions present in PDE2, PDE5, and PDE6. |
Baculovirus expression of FLAG-tagged full-length PDE9A; radiometric kinetic enzyme assays; inhibitor panel testing in vitro |
The Journal of biological chemistry |
High |
9624146
|
| 1998 |
PDE9A pre-mRNA is alternatively spliced into at least four variants (PDE9A1–A4) that differ at their 5′ exons, altering the N-terminal amino acid sequences while retaining the conserved catalytic domain; the gene spans ~122 kb and comprises 20 exons; the human and mouse orthologs share 93% amino acid identity. |
cDNA cloning, genomic sequencing, Northern blot, comparison of human and mouse cDNAs |
Human genetics |
High |
9856478
|
| 2003 |
PDE9A1 localizes exclusively to the nucleus of HEK293 cells and native T cells, dependent on a unique pat7 nuclear localization motif in its N-terminal extension, whereas PDE9A5 (a new splice variant lacking exons 2 and 5) localizes exclusively to the cytoplasm; both variants show similar high-affinity cGMP hydrolysis (Km ~0.25–0.39 µM) but different Vmax values. |
Transient transfection of HEK293 cells, subcellular fractionation, Western blot of T-cell nuclear/cytoplasmic fractions, kinetic enzyme assays, real-time quantitative PCR |
Gene |
High |
14527714
|
| 2018 |
PDE9A localizes to the membrane fraction in brain (and most organs) and also to the nuclear fraction in brain; isoform PDE9A2 predominates in non-brain tissues, while PDE9A6 and novel isoforms (PDE9X-100, PDE9X-120, PDE9X-175) are the predominant brain forms; subcellular compartmentalization is isoform-specific and brain-region-specific and changes with age. |
Subcellular fractionation of mouse and human brain tissue, isoform-specific detection, mRNA expression profiling across neurodevelopment |
Neurobiology of aging |
Medium |
29505961
|
| 2014 |
PDE9A is expressed in GABA-positive and GABA-negative amacrine cells and likely in certain ganglion cells of the inner retina; genetic knockout (PDE9A−/−) specifically prolongs and slows the photopic (cone pathway) ERG b-wave recovery without affecting scotopic responses, indicating PDE9A controls cGMP levels that modulate inhibitory processing within the cone pathway. |
LacZ reporter knock-in as PDE9A expression reporter, immunofluorescence, electroretinography in PDE9A knockout mice |
Frontiers in molecular neuroscience |
Medium |
25018695
|
| 2018 |
PDE9A hydrolyzes the non-canonical cyclic nucleotide cUMP with low affinity (Km ~401 µM) and high velocity (Vmax ~6 µmol/min/mg); docking studies identify H-bonds between the cUMP uridine moiety and Gln453/Asn405 (versus three H-bonds for cGMP guanosine moiety with Gln453), explaining substrate selectivity via a glutamine-switch mechanism; BAY 73-6691 inhibits cUMP hydrolysis with Ki ~590 nM. |
HPLC-coupled tandem mass spectrometry kinetic assay, computational docking to PDE9A crystal structure |
Naunyn-Schmiedeberg's archives of pharmacology |
Medium |
30443663
|
| 2025 |
The E3 ubiquitin ligase CHIP directly binds PDE9A, polyubiquitinates it, and targets it for autophagic degradation; loss-of-function CHIP mutations cause PDE9A accumulation, elevated cGMP hydrolysis, and impaired PKG phosphorylation of CHIP at Ser19; elevated PKA further inhibits PDE9A degradation; pharmacological PDE9A inhibition (BAY 73-6691) or virus-mediated CHIP restoration rescues mitophagy and reduces Purkinje neuron apoptosis in a CHIP-ataxia rodent model. |
Co-immunoprecipitation, polyubiquitination assays, preclinical rodent ataxia model, viral CHIP delivery, pharmacological inhibition, PKG/PKA phosphorylation readouts |
The EMBO journal |
High |
39806097
|
| 2025 |
NEURL1 (a RING-domain E3 ubiquitin ligase) promotes ubiquitination and proteasomal degradation of PDE9A in bladder cancer cells; RING-domain deletion of NEURL1 abolishes this effect; proteasome inhibitor MG-132 reverses NEURL1-induced PDE9A loss, confirming proteasomal targeting. |
Stable overexpression of WT and RING-deleted NEURL1 in 5637/RT-112 bladder cancer cells, Western blot, MG-132 rescue experiment, cell viability and apoptosis assays with PDE9A knockdown |
In vitro cellular & developmental biology. Animal |
Medium |
40442542
|
| 2017 |
PDE9A expression is upregulated during cardiac hypertrophy; PDE9A knockdown alleviates phenylephrine-induced hypertrophic responses in neonatal rat cardiomyocytes; PDE9A inhibition elevates intracellular cGMP, increases phospholamban (PLB) phosphorylation, and upregulates SERCA2a expression in cardiomyocytes and in an ISO-induced heart failure rat model. |
siRNA knockdown, pharmacological inhibition with C33(S) and PF-7943 in neonatal rat cardiomyocytes, in vivo rat heart failure model (ISO/AAC), echocardiography, cGMP measurement, Western blot |
Acta pharmacologica Sinica |
Medium |
28649129
|
| 2015 |
PDE9A inhibition (BAY73-6691) significantly increases gamma-globin (HBG) gene expression in K562 erythroleukaemic cells and reverses the elevated adhesive properties of sickle cell disease neutrophils, consistent with PDE9A controlling cGMP levels in haematopoietic cells. |
Pharmacological inhibition with BAY73-6691 in K562 cells and primary SCD neutrophils; gene expression analysis; adhesion assay |
British journal of haematology |
Medium |
18564357
|
| 2015 |
PDE9A inhibition (but not PDE2A inhibition) did not alter paired-pulse facilitation (PPF) in rat hippocampal CA1 slices, indicating PDE9A does not modulate presynaptic short-term plasticity under tested conditions, in contrast to PDE2A which acts presynaptically. |
Paired-pulse facilitation electrophysiology in acute rat hippocampal slices with selective PDE9A inhibitors |
Synapse (New York, N.Y.) |
Medium |
26178667
|
| 2020 |
In zebrafish oocytes, PDE9a maintains meiotic arrest by sustaining basal cGMP levels; overexpression of pde9aa mRNA in oocytes decreased cGMP and stimulated meiotic maturation, while PDE9a inhibition (BAY736691) also stimulated maturation via a gap-junction-dependent mechanism (blocking gap junctions abolished the effect); the stimulatory effect of elevated PDE9a during LH-induced maturation operates through oocyte cGMP hydrolysis. |
mRNA injection into zebrafish oocytes, cGMP measurement, pharmacological inhibition with BAY736691, gap junction blocker experiments, in vitro fertilization |
Biochemical and biophysical research communications |
Medium |
32826058
|
| 2021 |
PDE9A deficiency (Pde9a−/− mice) does not prevent chronic-hypoxic pulmonary hypertension; RV pressure, hypertrophy, and cGMP levels were not different between Pde9a−/− and wild-type mice after 3 weeks of hypoxic exposure, indicating PDE9A does not play a prominent role in the murine CH-PH model (in contrast to its established role in left ventricular pressure overload). |
Pde9a knockout mice, chronic hypoxia model, RV pressure measurement, cGMP quantification, VASP phosphorylation Western blot |
Physiological reports |
Medium |
34569183
|