Details for: PDE2A

Gene ID: 5138

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: PDE2A

Ensembl ID: ENSG00000186642

Description: phosphodiesterase 2A

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 14.86
    rCSI 36.1%
    PRS 81.03
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 14.14
    rCSI 43.57%
    PRS 94.32
  • L6b glutamatergic cortical neuron CL4023038
    CSI 11.97
    rCSI 37.42%
    PRS 84.19
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 10.37
    rCSI 39.2%
    PRS 83.27
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 6.43
    rCSI 37.86%
    PRS 83.56
  • sst GABAergic cortical interneuron CL4023017
    CSI 6.38
    rCSI 8.22%
    PRS 84.12
  • neuron CL0000540
    CSI 5.76
    rCSI 15.34%
    PRS 83.03
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 5.41
    rCSI 19.48%
    PRS 81.36
  • blood vessel endothelial cell CL0000071
    CSI 5.09
    rCSI 10.56%
    PRS 91.99
  • cardiac endothelial cell CL0010008
    CSI 4.82
    rCSI 19.46%
    PRS 93.81
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 3.9
    rCSI 4.85%
    PRS 81
  • inhibitory interneuron CL0000498
    CSI 3.84
    rCSI 8.86%
    PRS 86.18
  • intestinal tuft cell CL0019032
    CSI 3.69
    rCSI 5.63%
    PRS 94.28
  • sncg GABAergic cortical interneuron CL4023015
    CSI 3.62
    rCSI 5.82%
    PRS 84.14
  • brush cell CL0002204
    CSI 3.39
    rCSI 6.71%
    PRS 94.91
  • cerebral cortex neuron CL0010012
    CSI 3.26
    rCSI 13.27%
    PRS 87.43
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 2.99
    rCSI 5.02%
    PRS 83.19
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 2.92
    rCSI 6.97%
    PRS 84.96
  • retinal blood vessel endothelial cell CL0002585
    CSI 2.83
    rCSI 4.51%
    PRS 94.98
  • endothelial cell of periportal hepatic sinusoid CL0019021
    CSI 2.78
    rCSI 12.77%
    PRS 94.81
  • cerebral cortex endothelial cell CL1001602
    CSI 2.78
    rCSI 4.81%
    PRS 89.24
  • peripheral nervous system neuron CL2000032
    CSI 2.72
    rCSI 3.71%
    PRS 87.81
  • endothelial cell of vascular tree CL0002139
    CSI 2.71
    rCSI 14.82%
    PRS 89.81
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 2.58
    rCSI 5.59%
    PRS 83.87
  • VIP GABAergic cortical interneuron CL4023016
    CSI 2.53
    rCSI 3.02%
    PRS 83.18
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 2.08
    rCSI 6.51%
    PRS 85.96
  • GABAergic neuron CL0000617
    CSI 2.01
    rCSI 6.74%
    PRS 82.14
  • glutamatergic neuron CL0000679
    CSI 2
    rCSI 4.11%
    PRS 83.44
  • direct pathway medium spiny neuron CL4023026
    CSI 1.88
    rCSI 44.95%
    PRS 80.93
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.86
    rCSI 44.8%
    PRS 80.95
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 1.49
    rCSI 4.88%
    PRS 83.78
  • vein endothelial cell of respiratory system CL4033008
    CSI 1.28
    rCSI 8.78%
    PRS 95.62
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.22
    rCSI 2.15%
    PRS 82.49
  • vasa recta ascending limb cell CL1001131
    CSI 0.98
    rCSI 4.42%
    PRS 95.89
  • collagen secreting cell CL0000667
    CSI 0.78
    rCSI 4.45%
    PRS 95.45
  • central nervous system neuron CL2000029
    CSI 0.72
    rCSI 5.26%
    PRS 87.03

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.

Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [PDE2A](/details-gene/5138), or phosphodiesterase 2A, is a protein-coding gene located on chromosome 11q13.4. It encodes a dual-substrate phosphodiesterase that is uniquely stimulated by cyclic GMP (cGMP) to hydrolyze both cGMP and cyclic AMP (cAMP). This function positions [PDE2A](/details-gene/5138) as a critical integrator of the nitric oxide/cGMP and adrenergic/cAMP signaling pathways. **Overall**, expression data reveals its highest significance in distinct neuronal populations, particularly `L2/3-6 intratelencephalic projecting glutamatergic neurons` ([CL4023040](/details-cell/CL4023040)) and `L6b glutamatergic cortical neurons` ([CL4023038](/details-cell/CL4023038)), as well as in vascular `endothelial cells of pericentral hepatic sinusoids` ([CL0019022](/details-cell/CL0019022)). Clinically, loss-of-function mutations in [PDE2A](/details-gene/5138) have been associated with movement disorders, including early-onset hereditary chorea ([Link](https://doi.org/10.1002/mds.27286)) and syndromic paroxysmal dyskinesia ([Link](https://doi.org/10.1038/s41431-020-0641-9)), underscoring its essential role in neurological function. ## Cellular Roles and Expression Landscape The expression profile of [PDE2A](/details-gene/5138) indicates a highly specialized role in the central nervous and vascular systems. **Overall**, the gene shows prominent expression and significance across a range of neuronal subtypes, establishing it as a key regulator of neural signaling. It is most significant in various excitatory neurons, including `L2/3-6 intratelencephalic projecting glutamatergic neuron` ([CL4023040](/details-cell/CL4023040)), `L6b glutamatergic cortical neuron` ([CL4023038](/details-cell/CL4023038)), `near-projecting glutamatergic cortical neuron` ([CL4023012](/details-cell/CL4023012)), and `corticothalamic-projecting glutamatergic cortical neuron` ([CL4023013](/details-cell/CL4023013)). Its significance also extends to inhibitory interneurons such as `sst GABAergic cortical interneuron` ([CL4023017](/details-cell/CL4023017)) and `pvalb GABAergic cortical interneuron` ([CL4023018](/details-cell/CL4023018)), suggesting a broad role in modulating cortical circuit activity. In parallel, [PDE2A](/details-gene/5138) is a significant marker for endothelial cells from various tissues, including `endothelial cell of pericentral hepatic sinusoid` ([CL0019022](/details-cell/CL0019022)), `blood vessel endothelial cell` ([CL0000071](/details-cell/CL0000071)), and `cardiac endothelial cell` ([CL0010008](/details-cell/CL0010008)). This pattern suggests a conserved function in regulating vascular homeostasis and permeability. One splice variant of [PDE2A](/details-gene/5138) has been shown to localize to synaptic membranes, which is consistent with its high expression in `neurons` ([CL0000540](/details-cell/CL0000540)) and its role in neurotransmission ([Link](https://doi.org/10.1074/jbc.m109.017194)). ## Pathways and Molecular Function Functionally, [PDE2A](/details-gene/5138) is an enzyme with `3',5'-cgmp-stimulated cyclic-nucleotide phosphodiesterase activity` ([GO:0004118](https://www.ebi.ac.uk/QuickGO/term/GO:0004118)), enabling it to hydrolyze cAMP via its `3',5'-cyclic-amp phosphodiesterase activity` ([GO:0004115](https://www.ebi.ac.uk/QuickGO/term/GO:0004115)) in the presence of cGMP. This mechanism allows for intricate cross-talk between cGMP and cAMP signaling pathways. Its involvement is prominent in biological processes such as '[Cgmp-mediated signaling](https://www.ebi.ac.uk/QuickGO/term/GO:0019934)' and '[Negative regulation of camp-mediated signaling](https://www.ebi.ac.uk/QuickGO/term/GO:0043951)', which are fundamental to cellular communication. The high expression of [PDE2A](/details-gene/5138) in endothelial cells aligns with its annotated role in processes like '[Establishment of endothelial barrier](https://www.ebi.ac.uk/QuickGO/term/GO:0061028)' and the '[Negative regulation of vascular permeability](https://www.ebi.ac.uk/QuickGO/term/GO:0043116)'. Its function in the nervous system is supported by its localization to the `presynaptic membrane` ([GO:0042734](https://www.ebi.ac.uk/QuickGO/term/GO:0042734)) and involvement in '[Adenylate cyclase-inhibiting g protein-coupled receptor signaling pathway](https://www.ebi.ac.uk/QuickGO/term/GO:0007193)'. Reactome pathway analysis further situates [PDE2A](/details-gene/5138) within the broader contexts of '[Gpcr downstream signalling](https://reactome.org/content/detail/R-HSA-388396)' and '[Cgmp effects](https://reactome.org/content/detail/R-HSA-418457)', as well as '[Hemostasis](https://reactome.org/content/detail/R-HSA-109582)', which is consistent with its vascular expression. A specific isoform has also been implicated in regulating mitochondrial morphology and apoptosis ([Link](https://doi.org/10.7554/elife.21374)). ## Research Directions The well-defined molecular function of [PDE2A](/details-gene/5138) and its specific expression patterns in neuronal and endothelial cells, combined with its links to human disease, present several avenues for future research. Although the provided data does not show differential expression across contexts, published studies link [PDE2A](/details-gene/5138) to both neurological disorders and cancer, suggesting its role is highly context-dependent. Based on the available evidence, we propose the following testable hypotheses: 1. Given its high expression in `corticothalamic-projecting glutamatergic cortical neurons` ([CL4023013](/details-cell/CL4023013)) and the severe motor deficits caused by its loss-of-function ([Link](https://doi.org/10.1002/mds.27286)), we hypothesize that **[PDE2A](/details-gene/5138) acts as a critical signal integrator within corticothalamic circuits, where it fine-tunes synaptic transmission by mediating cross-talk between nitric oxide/cGMP and neuromodulator/cAMP pathways. Its absence leads to aberrant circuit activity and the manifestation of hyperkinetic movement disorders.** 2. Considering its high expression in endothelial cells and a report on its role in melanoma ([Link](https://doi.org/10.1016/j.cellsig.2014.03.031)), we hypothesize that **in the tumor microenvironment, [PDE2A](/details-gene/5138) activity in endothelial cells regulates tumor angiogenesis and metastasis by controlling local cyclic nucleotide levels, thereby modulating endothelial cell proliferation and barrier integrity.** To test the first hypothesis, a key experiment would be to generate a conditional knockout mouse model with [PDE2A](/details-gene/5138) specifically deleted in corticothalamic projection neurons. *In vitro* electrophysiological recordings from thalamic slices could then be used to assess how the loss of [PDE2A](/details-gene/5138) alters synaptic plasticity and responses to cGMP and cAMP agonists. These cellular-level findings should be correlated with *in vivo* deep-brain imaging and comprehensive behavioral phenotyping to assess motor control and coordination. As a therapeutic target, [PDE2A](/details-gene/5138) presents a dual opportunity. For cancers where its activity promotes growth or invasion, its enzymatic nature makes it a druggable target for inhibition. Highly selective inhibitors have already been developed ([Link](https://doi.org/10.1021/ja404449g)), though its widespread expression in healthy neuronal and vascular tissues raises significant concerns about on-target toxicity, likely requiring targeted delivery systems. Conversely, for the debilitating neurological disorders caused by loss-of-function mutations, strategies aimed at restoring or augmenting its function, such as gene therapy or the development of allosteric activators, could hold therapeutic promise, although this remains a formidable challenge.

Genular Protein ID: 1345664382

Symbol: PDE2A_HUMAN

Name: Cyclic GMP-stimulated phosphodiesterase

UniProtKB Accession Codes:

Database IDs:

Citations:

PubMed ID: 9210593

Title: Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3',5'-cyclic nucleotide phosphodiesterase.

PubMed ID: 9210593

DOI: 10.1016/s0378-1119(97)00046-2

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16554811

Title: Human chromosome 11 DNA sequence and analysis including novel gene identification.

PubMed ID: 16554811

DOI: 10.1038/nature04632

PubMed ID: 19632989

Title: Dual acylation of PDE2A splice variant 3: targeting to synaptic membranes.

PubMed ID: 19632989

DOI: 10.1074/jbc.m109.017194

PubMed ID: 19369195

Title: Large-scale proteomics analysis of the human kinome.

PubMed ID: 19369195

DOI: 10.1074/mcp.m800588-mcp200

PubMed ID: 20213681

Title: Strategy for comprehensive identification of human N-myristoylated proteins using an insect cell-free protein synthesis system.

PubMed ID: 20213681

DOI: 10.1002/pmic.200900783

PubMed ID: 24705027

Title: Role of phosphodiesterase 2 in growth and invasion of human malignant melanoma cells.

PubMed ID: 24705027

DOI: 10.1016/j.cellsig.2014.03.031

PubMed ID: 28463107

Title: PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling.

PubMed ID: 28463107

DOI: 10.7554/elife.21374

PubMed ID: 29392776

Title: A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea.

PubMed ID: 29392776

DOI: 10.1002/mds.27286

PubMed ID: 32467598

Title: Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia.

PubMed ID: 32467598

DOI: 10.1038/s41431-020-0641-9

PubMed ID: 32196122

Title: A homozygous splicing mutation in PDE2A in a family with atypical Rett syndrome.

PubMed ID: 32196122

DOI: 10.1002/mds.28023

PubMed ID: 15938621

Title: Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system.

PubMed ID: 15938621

DOI: 10.1021/bi047313h

PubMed ID: 19828435

Title: Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct.

PubMed ID: 19828435

DOI: 10.1073/pnas.0907635106

PubMed ID: 23899287

Title: X-ray crystal structure of phosphodiesterase 2 in complex with a highly selective, nanomolar inhibitor reveals a binding-induced pocket important for selectivity.

PubMed ID: 23899287

DOI: 10.1021/ja404449g

Sequence Information:

  • Length: 941
  • Mass: 105717
  • Checksum: 9797609B487FD64E
  • Sequence:
  • MGQACGHSIL CRSQQYPAAR PAEPRGQQVF LKPDEPPPPP QPCADSLQDA LLSLGSVIDI 
    SGLQRAVKEA LSAVLPRVET VYTYLLDGES QLVCEDPPHE LPQEGKVREA IISQKRLGCN 
    GLGFSDLPGK PLARLVAPLA PDTQVLVMPL ADKEAGAVAA VILVHCGQLS DNEEWSLQAV 
    EKHTLVALRR VQVLQQRGPR EAPRAVQNPP EGTAEDQKGG AAYTDRDRKI LQLCGELYDL 
    DASSLQLKVL QYLQQETRAS RCCLLLVSED NLQLSCKVIG DKVLGEEVSF PLTGCLGQVV 
    EDKKSIQLKD LTSEDVQQLQ SMLGCELQAM LCVPVISRAT DQVVALACAF NKLEGDLFTD 
    EDEHVIQHCF HYTSTVLTST LAFQKEQKLK CECQALLQVA KNLFTHLDDV SVLLQEIITE 
    ARNLSNAEIC SVFLLDQNEL VAKVFDGGVV DDESYEIRIP ADQGIAGHVA TTGQILNIPD 
    AYAHPLFYRG VDDSTGFRTR NILCFPIKNE NQEVIGVAEL VNKINGPWFS KFDEDLATAF 
    SIYCGISIAH SLLYKKVNEA QYRSHLANEM MMYHMKVSDD EYTKLLHDGI QPVAAIDSNF 
    ASFTYTPRSL PEDDTSMAIL SMLQDMNFIN NYKIDCPTLA RFCLMVKKGY RDPPYHNWMH 
    AFSVSHFCYL LYKNLELTNY LEDIEIFALF ISCMCHDLDH RGTNNSFQVA SKSVLAALYS 
    SEGSVMERHH FAQAIAILNT HGCNIFDHFS RKDYQRMLDL MRDIILATDL AHHLRIFKDL 
    QKMAEVGYDR NNKQHHRLLL CLLMTSCDLS DQTKGWKTTR KIAELIYKEF FSQGDLEKAM 
    GNRPMEMMDR EKAYIPELQI SFMEHIAMPI YKLLQDLFPK AAELYERVAS NREHWTKVSH 
    KFTIRGLPSN NSLDFLDEEY EVPDLDGTRA PINGCCSLDA E

Genular Protein ID: 4152252911

Symbol: Q8IW54_HUMAN

Name: N/A

UniProtKB Accession Codes:

Database IDs:

Citations:

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

Sequence Information:

  • Length: 941
  • Mass: 105649
  • Checksum: 93028FC28CB54D6B
  • Sequence:
  • MGQACGHSIL CRSQQYPAAR PAEPRGQQVF LKPDEPPPPP QQCADSLQDA LLSLGSVIDI 
    SGLQRAVKEA LSAVLPRVET VYTYLLDGES QLVCEDPPHE LPQEGKVREA IISQKRLGCN 
    GLGFSDLPGK PLARLVAPLA PDTQVLVMPL ADKEAGAVAA VILVHCGQLS DNEEWSLQAV 
    EKHTLVALRR VQVLQQRGPR EAPRAVQNPP EGTAEDQKGG AAYTDRDRKI LQLCGELYDL 
    DASSLQLKVL QYLQQETRAS RCCLLLVSED NLQLSCKVIG DKVLGEEVSF PLTGCLGQVV 
    EDKKSIQLKD LTSEDVQQLQ SMLGCELQAM LCVPVISRAT DQVVALACAF NKLEGDLFTD 
    EDEHVIQHCF HYTSTVLTST LAFQKEQKLK CECQALLQVA KNLFTHLDDV SVLLQEIITE 
    ARNLSNAEIC SVFLLDQNEL VAKVFDGGVV DDESYEIRIP ADQGIAGHVA TTGQILNIPD 
    AYAHPLFYRG VDDSTGFRTR NILCFPIKNE NQEVIGVAEL VNKINGPWFS KFDEDLATAF 
    SIYCGISIAH SLLYKKVNEA QYRSHLANEM MMYHMKVSDD EYTKLLHDGI QPVAAIDSNF 
    ASFTYTPRSL PEDDTSMAIL SMLQDMNFIN NYKIDCPTLA RFCLMVKKGY RDPPYHNWMH 
    AFSVSHFCYL LYKNLELTNY LEDIEIFALF ISCMCHDLDH RGTNNSFQVA SKSVLAALYS 
    SEGSVMERHH FAQAIAILNT HGCNIFDHFS RKDYQRMLDL MRDIILATDL AHHLRIFKDL 
    QKMAEVGYDR NNKQHHRLLL CLLMTSCDLS DQTKGWKTTR KIAELIYKEF FSQGDLEKAM 
    GNRPMEMMDR EKAYIPELQI SFMEHIAMPI YKLLQDLFPK AAELYERVAS NGEHWTKVSH 
    KFTIRGIPSN NSLDFLDEEY EVPDLDGTRA PINGCCSLDA E