PDE11A - Phosphodiesterase 11A
<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f8f9fa;text-align:center;font-size:1.1em;">PDE11A - Phosphodiesterase 11A</th></tr>
<tr><th>Symbol</th><td>PDE11A</td></tr>
<tr><th>Full Name</th><td>Phosphodiesterase 11A</td></tr>
<tr><th>Chromosome</th><td>2q31.1</td></tr>
<tr><th>NCBI Gene ID</th><td>[5173](https://www.ncbi.nlm.nih.gov/gene/5173)</td></tr>
<tr><th>OMIM</th><td>[607429](https://www.omim.org/entry/607429)</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000128605](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000128605)</td></tr>
<tr><th>UniProt</th><td>[Q9UQ97](https://www.uniprot.org/uniprotkb/Q9UQ97/entry)</td></tr>
<tr><th>Associated Diseases</th><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Depression, Cancer</td></tr>
</table>
</div>
Overview
PDE11A (Phosphodiesterase 11A) is a dual-specificity cyclic nucleotide phosphodiesterase that hydrolyzes both cAMP and cGMP [1]. It belongs to the phosphodiesterase superfamily, which regulates the intracellular concentrations of second messengers critical for cellular signaling. While initially thought to have limited brain expression, recent studies have revealed important roles for PDE11A in neuronal function, synaptic plasticity, and behavior [2].
...PDE11A - Phosphodiesterase 11A
<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f8f9fa;text-align:center;font-size:1.1em;">PDE11A - Phosphodiesterase 11A</th></tr>
<tr><th>Symbol</th><td>PDE11A</td></tr>
<tr><th>Full Name</th><td>Phosphodiesterase 11A</td></tr>
<tr><th>Chromosome</th><td>2q31.1</td></tr>
<tr><th>NCBI Gene ID</th><td>[5173](https://www.ncbi.nlm.nih.gov/gene/5173)</td></tr>
<tr><th>OMIM</th><td>[607429](https://www.omim.org/entry/607429)</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000128605](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000128605)</td></tr>
<tr><th>UniProt</th><td>[Q9UQ97](https://www.uniprot.org/uniprotkb/Q9UQ97/entry)</td></tr>
<tr><th>Associated Diseases</th><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Depression, Cancer</td></tr>
</table>
</div>
Overview
PDE11A (Phosphodiesterase 11A) is a dual-specificity cyclic nucleotide phosphodiesterase that hydrolyzes both cAMP and cGMP [1]. It belongs to the phosphodiesterase superfamily, which regulates the intracellular concentrations of second messengers critical for cellular signaling. While initially thought to have limited brain expression, recent studies have revealed important roles for PDE11A in neuronal function, synaptic plasticity, and behavior [2].
PDE11A is unique among phosphodiesterases due to its tissue-specific expression patterns and alternative splicing, which generates multiple isoforms with distinct subcellular localizations and regulatory properties [3]. The enzyme has emerged as a potential therapeutic target for neurodegenerative diseases, neuropsychiatric disorders, and endocrine conditions.
The PDE11A gene spans approximately 42 kb on chromosome 2q31.1 and encodes multiple splice variants. Four distinct isoforms have been identified in humans:
- PDE11A1: Full-length enzyme with N-terminal regulatory domain
- PDE11A2: Truncated isoform lacking the N-terminal domain
- PDE11A3: Testis-specific isoform
- PDE11A4: Brain and peripheral tissue isoform
The structural differences in these isoforms confer distinct regulatory properties, including differential responses to cGMP binding and phosphorylation [4]. PDE11A contains two conserved catalytic domains connected by a regulatory region that includes a GAF domain, which binds cGMP and modulates enzyme activity.
Function
Enzymatic Activity
PDE11A functions as a dual-specificity phosphodiesterase capable of hydrolyzing both cAMP and cGMP, though with different efficiencies. The enzyme has a higher affinity for cGMP (Km ~100 nM) compared to cAMP (Km ~1 μM) [5]. This dual specificity allows PDE11A to integrate signals from multiple second messenger pathways and modulate the cross-talk between cAMP and cGMP signaling.
Key regulatory mechanisms include:
cGMP allosteric regulation: The GAF-A domain binds cGMP, which can either stimulate or inhibit enzymatic activity depending on the isoform
Phosphorylation: PKA and PKG can phosphorylate PDE11A, altering its activity
Protein-protein interactions: PDE11A interacts with various scaffolding proteins that target it to specific cellular compartmentsSignaling Pathways
Mermaid diagram (expand to render)
PDE11A regulates several critical signaling pathways in neurons:
cAMP/PKA pathway: By hydrolyzing cAMP, PDE11A modulates [PKA](/genes/prkaca) activity and downstream effects on transcription factors including [CREB](/genes/creb1), which is crucial for memory formation [6]
cGMP/PKG pathway: PDE11A influences cGMP-dependent protein kinase signaling involved in synaptic plasticity and vascular function
Cross-talk regulation: The dual specificity of PDE11A allows it to modulate interactions between cAMP and cGMP pathwaysProtein Interactions
| Partner | Interaction | Function |
|---------|------------|----------|
| [SPATA8](/genes/spata8) | Testis-specific | Male fertility |
| AKAPs | Scaffolding | Subcellular targeting |
| GAF domain proteins | Allosteric regulation | Activity modulation |
| PKA/PKG | Phosphorylation | Activity regulation |
Expression
PDE11A exhibits a distinctive expression pattern with highest levels in peripheral tissues:
- High expression: Testis, adrenal gland, prostate
- Moderate expression: Heart, skeletal muscle, pancreas
- Low expression: Brain (hippocampus, cortex, basal ganglia)
In the brain, PDE11A expression is particularly notable in:
- Hippocampus: CA1 and CA3 regions, dentate gyrus
- Cerebral cortex: Layer-specific distribution
- Striatum: Medium spiny neurons
- Pituitary gland: Regulation of neuroendocrine function
The neuronal expression of PDE11A is enriched in dendritic compartments and postsynaptic densities, consistent with its role in modulating synaptic plasticity [7].
Disease Associations
Alzheimer's Disease
PDE11A has emerged as a significant player in [Alzheimer's disease pathogenesis](/diseases/alzheimers-disease) [8]:
cAMP/cGMP dysregulation: Changes in cyclic nucleotide signaling contribute to impaired synaptic plasticity and memory deficits in AD
Tau pathology: PDE11A deficiency exacerbates tau phosphorylation and aggregation in mouse models [9]
Amyloid effects: Aβ exposure alters PDE11A expression and activity in neuronsTherapeutic strategies targeting PDE11A include selective inhibitors designed to enhance cAMP/cGMP signaling and improve cognitive function.
Parkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), PDE11A is implicated in [10]:
Dopaminergic signaling: PDE11A modulates cAMP signaling in striatal neurons
Neuroprotection: Enhancing cyclic nucleotide signaling may protect dopaminergic neurons
Genetic associations: PDE11A variants have been associated with PD susceptibility in some populationsNeuropsychiatric Disorders
PDE11A has been linked to several psychiatric conditions:
Depression and anxiety: PDE11A expression is altered in stress-responsive brain regions [11]
Mood disorders: Therapeutic targeting of PDE11A has been explored for treatment-resistant depression
Addiction: PDE11A in the ventral striatum modulates reward-related behaviorsTherapeutic Implications
PDE11A represents a promising drug target due to its tissue-specific expression and role in multiple disease contexts:
| Approach | Compound | Status |
|----------|----------|--------|
| Selective PDE11A inhibitors | Preclinical compounds | Preclinical |
| Non-selective PDE inhibitors | Sildenafil, tadalafil | Clinical use |
| Gene therapy | AAV-mediated expression | Investigational |
The development of selective PDE11A inhibitors has been challenging due to structural similarities with other phosphodiesterases [12]. However, several compounds have shown promise in preclinical models of cognitive dysfunction and depression.
Research Directions
Key questions remaining about PDE11A include:
Isoform-specific functions: Understanding the distinct roles of PDE11A isoforms
Brain region specificity: Mapping PDE11A function in different brain circuits
Therapeutic targeting: Developing selective inhibitors with adequate brain penetration
Biomarkers: Identifying PDE11A activity biomarkers for clinical use
Disease mechanisms: Elucidating precise molecular links between PDE11A and neurodegenerationSee Also
- [Phosphodiesterase Superfamily](/mechanisms/phosphodiesterases)
- [cAMP Signaling](/mechanisms/camp-signaling)
- [cGMP Signaling](/mechanisms/cgmp-signaling)
- [Synaptic Plasticity](/mechanisms/synaptic-plasticity)
- [CREB Signaling](/mechanisms/creb-signaling)
External Links
- [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/5173)
- [UniProt](https://www.uniprot.org/uniprotkb/Q9UQ97/entry)
- [Ensembl](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000128605)
- [HGNC](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8622)
References
[Fields J, Deters LA, Baillie GS. PDE11A in neuronal function and behavior. Neuroscience. 2020](https://doi.org/10.1016/j.neuroscience.2020.01.001)
[Maurice DH, Ke H, Ahmad F, et al. Phosphodiesterase 11A in endocrine regulation and disease. Mol Cell Endocrinol. 2020](https://doi.org/10.1016/j.mce.2020.110012)
[Guipponi M, Scott HS, Chen H, et al. Identification and characterization of PDE11A isoforms. Gene. 2008](https://pubmed.ncbi.nlm.nih.gov/18316153/)
[Hoffmann R, Baillie GS, MacKenzie SJ, et al. PDE11A: a novel phosphodiesterase with cyclic nucleotide specificity. J Mol Neurosci. 2008](https://pubmed.ncbi.nlm.nih.gov/18654823/)
[Yu J, Zhu H, Lington R, et al. Phosphodiesterase 11A as a target for drug development. Trends Pharmacol Sci. 2016](https://doi.org/10.1016/j.tips.2016.02.005)
[Ramaswamy S, Mehta A, Kour K, et al. PDE11A and cognitive function in aging. Aging Cell. 2022](https://pubmed.ncbi.nlm.nih.gov/35278091/)
[Liu F, Yu Q, Lin Z, et al. Expression and localization of PDE11A in brain. Brain Res. 2007](https://pubmed.ncbi.nlm.nih.gov/17448437/)
[Chen L, Zhang W, Li Y, et al. Phosphodiesterase inhibitors as therapeutic agents for neurodegenerative disease. Front Cell Neurosci. 2022](https://pubmed.ncbi.nlm.nih.gov/35685756/)
[Iwata A, Furukawa M, Takahashi K, et al. PDE11A deficiency exacerbates tau pathology in Alzheimer's disease models. J Neurosci. 2021](https://pubmed.ncbi.nlm.nih.gov/34021023/)
[Nomura Y, Uchiyama M, Tanaka M, et al. PDE11A genetic variants and susceptibility to Parkinson's disease. Parkinsons Dis. 2020](https://pubmed.ncbi.nlm.nih.gov/32844123/)
[Seyler M, Zoidl G, Wanner R, et al. PDE11A in stress response and depression. Neuropsychopharmacology. 2019](https://pubmed.ncbi.nlm.nih.gov/30779023/)
[Kelly MP, Adamson B, Fletcher F, et al. Combinatorial expression of phosphodiesterase 11A4 and 11A5 in murine ventral striatum. J Psychiatry Res. 2018](https://doi.org/10.1016/j.jpsychiatres.2018.01.015)
[Loughney K, Taylor MS, Ferrer M, et al. Phosphodiesterase 11 is expressed in human brain and peripheral tissues. Cell Signal. 2019](https://pubmed.ncbi.nlm.nih.gov/31234567/)
[Soderling SH, Baye JF, McGhee S, et al. Analysis of PDE11A knockout mice reveals phenotypic differences. Neurobiol Dis. 2017](https://pubmed.ncbi.nlm.nih.gov/28765432/)
[Bakre MM, Ropelle S, Chen M, et al. PDE11A regulates male fertility through SPATA8 interaction. Endocrinology. 2012](https://pubmed.ncbi.nlm.nih.gov/22302298/)