PDE2A

Official Full Name

phosphodiesterase 2A

Organism

Homo sapiens

GeneID

5138

Background

Enables several functions, including 3',5'-cyclic-nucleotide phosphodiesterase activity; anion binding activity; and metal ion binding activity. Involved in several processes, including cellular response to cytokine stimulus; regulation of signal transduction; and regulation of vascular permeability. Located in several cellular components, including cytosol; mitochondrial membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

PDE2A1; PED2A4; cGSPDE; CGS-PDE; IDDPADS;

Bio Chemical Class

Phosphoric diester hydrolase

Protein Sequence

MGQACGHSILCRSQQYPAARPAEPRGQQVFLKPDEPPPPPQPCADSLQDALLSLGSVIDISGLQRAVKEALSAVLPRVETVYTYLLDGESQLVCEDPPHELPQEGKVREAIISQKRLGCNGLGFSDLPGKPLARLVAPLAPDTQVLVMPLADKEAGAVAAVILVHCGQLSDNEEWSLQAVEKHTLVALRRVQVLQQRGPREAPRAVQNPPEGTAEDQKGGAAYTDRDRKILQLCGELYDLDASSLQLKVLQYLQQETRASRCCLLLVSEDNLQLSCKVIGDKVLGEEVSFPLTGCLGQVVEDKKSIQLKDLTSEDVQQLQSMLGCELQAMLCVPVISRATDQVVALACAFNKLEGDLFTDEDEHVIQHCFHYTSTVLTSTLAFQKEQKLKCECQALLQVAKNLFTHLDDVSVLLQEIITEARNLSNAEICSVFLLDQNELVAKVFDGGVVDDESYEIRIPADQGIAGHVATTGQILNIPDAYAHPLFYRGVDDSTGFRTRNILCFPIKNENQEVIGVAELVNKINGPWFSKFDEDLATAFSIYCGISIAHSLLYKKVNEAQYRSHLANEMMMYHMKVSDDEYTKLLHDGIQPVAAIDSNFASFTYTPRSLPEDDTSMAILSMLQDMNFINNYKIDCPTLARFCLMVKKGYRDPPYHNWMHAFSVSHFCYLLYKNLELTNYLEDIEIFALFISCMCHDLDHRGTNNSFQVASKSVLAALYSSEGSVMERHHFAQAIAILNTHGCNIFDHFSRKDYQRMLDLMRDIILATDLAHHLRIFKDLQKMAEVGYDRNNKQHHRLLLCLLMTSCDLSDQTKGWKTTRKIAELIYKEFFSQGDLEKAMGNRPMEMMDREKAYIPELQISFMEHIAMPIYKLLQDLFPKAAELYERVASNREHWTKVSHKFTIRGLPSNNSLDFLDEEYEVPDLDGTRAPINGCCSLDAE

Open

Disease

Inborn purine/pyrimidine/nucleotide metabolism error, Indeterminate colitis, Irritable bowel syndrome, Mood disorder

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

1 +

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Detailed Information

The PDE2A gene is located on human chromosome 11q13.4 and encodes Phosphodiesterase 2A, a dual-substrate cyclic nucleotide hydrolase. Its protein structure comprises an N-terminal GAF domain (responsible for cGMP-binding regulation) and a C-terminal catalytic domain (which hydrolyzes cAMP and cGMP). PDE2A is unique due to its allosteric activation mechanism—binding of cGMP to the GAF domain enhances the catalytic domain's activity by 10 to 30 times, preferentially hydrolyzing cAMP (Km = 30 μM). This forms a "cGMP-mediated inhibition of cAMP" negative feedback loop.

There are three isoforms of PDE2A—PDE2A1, PDE2A2, and PDE2A3—which are differentially distributed across subcellular compartments:

PDE2A1: Localized in the cytoplasm, it regulates spatial signaling of PKA.
PDE2A2: Anchored to the outer mitochondrial membrane via N-terminal palmitoylation, it modulates the activity of respiratory chain complexes.
PDE2A3: Located around the nucleus, it influences phosphorylation of transcription factors.

In neurons, PDE2A is enriched in the postsynaptic density, where it dynamically hydrolyzes cAMP and cGMP to regulate synaptic plasticity. A research team led by Bardoni in France demonstrated that the PDE2A2 isoform helps maintain mitochondrial homeostasis by limiting PKA activity and stabilizing Drp1 phosphorylation, thereby preventing excessive mitochondrial fission and neuronal apoptosis. In endothelial cells, PDE2A degrades cGMP to dampen NO signaling, increase vascular permeability, and promote tumor angiogenesis.

Disease Mechanisms and Clinical Associations

1. Neurological Disorders

Genome-wide association studies (GWAS) have linked PDE2A mutations to several cognitive disorders:

Autism Spectrum Disorder (ASD): A missense mutation (p.R552Q) in PDE2A results in a 60% reduction in enzymatic activity, leading to cAMP accumulation in cortical neurons. This hyperactivates PKA and abnormally phosphorylates GluA1 receptors, impairing synaptic maturation.
Paroxysmal Movement Disorders: A p.G305V mutation disrupts the GAF domain's allosteric regulation, disturbing cGMP signaling in cerebellar Purkinje cells and triggering chorea-like motor symptoms.

In animal models of ASD induced by valproic acid, PDE2A expression is downregulated. Administration of a PDE2A activator (BAY60-7550) reverses social deficits and repetitive stereotyped behaviors.

2. Tumor Progression and Drug Resistance

PDE2A functions as a tumor suppressor in gastrointestinal cancers:

Expression Downregulation: In liver, gastric, and pancreatic cancers, PDE2A mRNA levels are reduced to 30–50% of adjacent normal tissue levels (based on TIMER database analyses).
Prognostic Value: In hepatocellular carcinoma, patients with high PDE2A expression show a 5-year survival rate of 48.2%, significantly higher than the 19.0% in the low-expression group. A similar survival benefit is observed in pancreatic cancer (extended by 8.7 months).

Mechanistically, loss of PDE2A leads to cAMP accumulation, which activates the EPAC/Rap1 pathway and enhances tumor cell invasiveness. Crucially, PDE2A contributes to chemotherapy resistance. In the cisplatin-resistant small cell lung cancer cell line H446/CDDP, PDE2A is specifically overexpressed. Silencing PDE2A reduces the IC50 of cisplatin by 3.6-fold, suggesting that it helps maintain the resistant phenotype via the cAMP-CREB axis.

Targeted Drug Development

Both inhibitors and activators of PDE2A are under development:

These raise intracellular cAMP and cGMP levels to enhance cognitive function. In preclinical ASD models, ND7001 restores 70% of hippocampal long-term potentiation (LTP) and improves performance in memory tasks.
Used in conditions like tuberous sclerosis, where they inhibit excessive PKA activation and abnormal neurite outgrowth. A Phase II clinical trial showed a 25% improvement in executive function scores.

A key challenge is isoform selectivity, as conventional drugs cannot differentiate between PDE2A1, PDE2A2, and PDE2A3. New allosteric modulators, such as TAK-915, target the GAF domain for selective activation of the A2 isoform. In Parkinson's disease models, TAK-915 improves motor coordination without cardiovascular side effects.

References:

Trabanco AA, Buijnsters P, Rombouts FJ. Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present). Expert Opin Ther Pat. 2016 Aug;26(8):933-46.
Erro R, Mencacci NE, Bhatia KP. The Emerging Role of Phosphodiesterases in Movement Disorders. Mov Disord. 2021 Oct;36(10):2225-2243.
Delhaye S, Bardoni B. Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders. Mol Psychiatry. 2021 Sep;26(9):4570-4582.
Santana LS, Guimaraes AG, Almeida MQ. Pathogenesis of Primary Aldosteronism: Impact on Clinical Outcome. Front Endocrinol (Lausanne). 2022 Jun 23;13:927669.

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