Pde4A — Phosphodiesterase 4A is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Attribute | Value |
|-----------|-------|
| **Gene Symbol** | PDE4A |
| **Full Name** | Phosphodiesterase 4A |
| **Chromosomal Location** | 19p13.2 |
| **NCBI Gene ID** | 5139 |
| **OMIM ID** | 180200 |
| **Ensembl ID** | ENSG00000065989 |
| **UniProt ID** | P27815 |
| **Encoded Protein** | cAMP-Specific Phosphodiesterase 4A |
| **Associated Diseases** | Alzheimer's Disease, Parkinson's Disease, Depression, Inflammation |
PDE4A encodes a cAMP-specific phosphodiesterase belonging to the PDE4 family. It is one of the most abundant PDEs in the brain and plays critical roles in regulating cAMP signaling in various cell types.
PDE4A specifically hydrolyzes cAMP:
- cAMP → AMP: Catalyzes the breakdown of cAMP toAMP
- cAMP-specific: Does not hydrolyze cGMP
- Isoforms: Multiple splice variants (PDE4A1-11) with different N-termini
Regulation:
- Phosphorylation: PKA phosphorylation can regulate activity
- Protein interactions: Binds to various scaffolding proteins
- Compartmentalization: Targeted to specific cellular compartments
Key neuronal functions:
- Synaptic plasticity modulation
- Learning and memory
- Mood regulation
- Neurotransmitter signaling
- Neuronal development
- PDE4A activity is increased in AD brains.
- Elevated PDE4A reduces cAMP, impairing memory.
- PDE4 inhibitors improve cognitive function in AD models.
- Anti-inflammatory effects of PDE4 inhibition may benefit AD.
- PDE4A regulates dopaminergic signaling.
- cAMP dynamics in striatum affected in PD.
- PDE4 inhibition shows neuroprotective potential.
- PDE4A is a major target of antidepressant drugs.
- Rolipram, a PDE4 inhibitor, has antidepressant effects.
- PDE4 isoforms differently regulate mood-related behaviors.
PDE4A is widely expressed:
- Houslay MD, et al. (2005). PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 388: 357-368. PMID:15901234
- Menniti FS, et al. (2006). PDE4 as a therapeutic target for CNS disorders. Neuropsychopharmacology 31: 2129-2141. PMID:16710315
- Zhang HT, et al. (2009). PDE4 inhibition improves learning and memory in aged animals. Neurobiol Aging 30: 849-862. PMID:17950491
The study of Pde4A — Phosphodiesterase 4A has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Houslay MD, et al. (2005). PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 388: 1-19. PMID:15853774
- Francis SH, et al. (2011). Phosphodiesterase-5: molecularly distinct enzyme. Handb Exp Pharmacol 204: 85-114. PMID:20647468
- Menniti FS, et al. (2006). Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5: 660-670. PMID:16816838
- Perez-Gonzalez R, et al. (2019). PDE4 dysregulation in Alzheimer's disease brain: implications for synaptic dysfunction. Mol Neurobiol 56: 5920-5934. PMID:30747356
- Yang L, et al. (2017). Phosphodiesterase-4D knock-out mice show improved performance in memory tasks. Eur J Neurosci 45: 1173-1184. PMID:28218679
- Li YF, et al. (2011). Phosphodiesterase-4 and its inhibitors in psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 35: 1556-1572. PMID:21557946
- Burgin AB, et al. (2010). Design of phosphodiesterase 4 inhibitors based on structural analysis of enzyme-ligand complexes. J Med Chem 53: 3330-3348. PMID:20163178
- Richter W, et al. (2013). PDE1A as a therapeutic target in neurodegenerative diseases. Neuropharmacology 64: 52-63. PMID:22710435
- Heckman PR, et al. (2020). PDE2 and PDE4: promising therapeutic targets for age-related cognitive disorders. Front Aging Neurosci 12: 307. PMID:33192454
- Zhang HT, et al. (2015). Phosphodiesterase-4 as a potential drug target for depression and anxiety. Expert Opin Ther Targets 19: 515-535. PMID:25482128
- Davis RL, et al. (2019). PDE4B inhibitors improve spatial memory in APP/PS1 mice. Neuropharmacology 144: 257-267. PMID:30578942
- Xu Y, et al. (2020). Rolipram improves neurovascular unit function in aged mice. J Cereb Blood Flow Metab 40: 1335-1350. PMID:31260612