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Phosphodiesterase function and regulation
Research Guide
What is Phosphodiesterase function and regulation?
Phosphodiesterase function and regulation refers to the molecular mechanisms by which cyclic nucleotide phosphodiesterases (PDEs) hydrolyze cAMP and cGMP to terminate signaling, with regulation occurring through multiple isoforms, compartmentalized localization, and interactions with G protein-coupled receptors.
There are 20,502 works on phosphodiesterase function and regulation. Multiple PDE isoforms exist, each with distinct substrate specificities, regulatory domains, and tissue distributions, as detailed in early foundational studies. Recent understanding emphasizes their roles in compartmentalized cAMP signaling and therapeutic targeting in diseases like schizophrenia and cardiac dysfunction.
Topic Hierarchy
Research Sub-Topics
Phosphodiesterase Isoform Functions
This sub-topic characterizes PDE1-11 families' substrate specificity, tissue distribution, and signaling roles. Researchers use knockouts, crystallography, and compartmentalization studies.
cAMP Compartmentalized Signaling
This sub-topic investigates microdomains where PDEs shape local cAMP gradients for pathway specificity. Researchers apply FRET biosensors, AKAP scaffolds, and modeling.
PDE Inhibitors in Cardiovascular Disease
This sub-topic evaluates PDE3/5 inhibitors for heart failure, pulmonary hypertension, and contractility. Researchers conduct trials, pharmacodynamics, and resistance mechanisms.
PDEs in Neurodegenerative Disorders
This sub-topic links PDE dysregulation to Alzheimer's pathology, cognition, and tauopathy via cAMP/CREB. Researchers test isoform-selective drugs in models and biomarkers.
PDE Regulation by G Protein-Coupled Receptors
This sub-topic dissects GPCR-PDE crosstalk in feedback loops and cross-talk. Researchers map phosphorylation sites, β-arrestin roles, and dynamic modeling.
Why It Matters
Phosphodiesterases regulate cAMP and cGMP levels critical for cardiac function, neuronal development, and psychiatric disorders. Beavo (1995) in "Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms" showed that isoform diversity enables specific inhibition for therapies, with sildenafil targeting PDE5 for erectile dysfunction and pulmonary hypertension. Bender and Beavo (2006) in "Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use" highlighted clinical applications of PDE inhibitors in heart failure and Alzheimer's disease treatment. Millar (2000) in "Disruption of two novel genes by a translocation co-segregating with schizophrenia" linked DISC1 and PDE4B disruptions to schizophrenia genetics, supporting PDE4 inhibitors like rolipram for mood disorders.
Reading Guide
Where to Start
"Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms" by Joseph A. Beavo (1995), as it provides the foundational overview of isoform diversity and functional implications with 1777 citations.
Key Papers Explained
Beavo (1995) in "Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms" establishes isoform multiplicity, which Bender and Beavo (2006) in "Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use" (1755 citations) extends to molecular regulation and inhibitors. Conti and Beavo (2007) in "Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling" (1168 citations) builds on these by detailing signaling integration. Millar (2000) in "Disruption of two novel genes by a translocation co-segregating with schizophrenia" (1261 citations) applies this to disease genetics.
Paper Timeline
Most-cited paper highlighted in red. Papers ordered chronologically.
Advanced Directions
Current research emphasizes PDE roles in schizophrenia genetics via DISC1-PDE4B interactions and compartmentalized signaling for Alzheimer's and cardiac therapies, as synthesized in top-cited reviews like Bender and Beavo (2006) and Conti and Beavo (2007). No recent preprints or news available.
Papers at a Glance
| # | Paper | Year | Venue | Citations | Open Access |
|---|---|---|---|---|---|
| 1 | Cyclic nucleotide phosphodiesterases: functional implications ... | 1995 | Physiological Reviews | 1.8K | ✕ |
| 2 | Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to ... | 2006 | Pharmacological Reviews | 1.8K | ✕ |
| 3 | A Family of cAMP-Binding Proteins That Directly Activate Rap1 | 1998 | Science | 1.4K | ✕ |
| 4 | Disruption of two novel genes by a translocation co-segregatin... | 2000 | Human Molecular Genetics | 1.3K | ✓ |
| 5 | Guanylyl Cyclases and Signaling by Cyclic GMP | 2000 | Pharmacological Reviews | 1.2K | ✕ |
| 6 | Chronic antidepressant administration increases the expression... | 1996 | Journal of Neuroscience | 1.2K | ✓ |
| 7 | Biochemistry and Physiology of Cyclic Nucleotide Phosphodieste... | 2007 | Annual Review of Bioch... | 1.2K | ✕ |
| 8 | Type-Specific Regulation of Adenylyl Cyclase by G Protein βγ S... | 1991 | Science | 1.1K | ✕ |
| 9 | Multiple cyclic nucleotide phosphodiesterase activities from r... | 1971 | Biochemistry | 1.1K | ✕ |
| 10 | cAMP Activates MAP Kinase and Elk-1 through a B-Raf- and Rap1-... | 1997 | Cell | 1.1K | ✓ |
Frequently Asked Questions
What are the main isoforms of cyclic nucleotide phosphodiesterases?
Cyclic nucleotide phosphodiesterases comprise over 100 isoforms grouped into families with specific cAMP or cGMP preferences. Beavo (1995) in "Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms" describes their regulatory domains and tissue-specific expression. These isoforms allow compartmentalized signaling control in cells.
How do phosphodiesterases regulate cAMP signaling?
Phosphodiesterases hydrolyze cAMP to 5'-AMP, terminating its signaling effects. Conti and Beavo (2007) in "Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling" explain that PDEs integrate with adenylyl cyclases and G proteins for precise spatiotemporal control. This regulation affects processes from gene expression to neurotransmission.
What role do PDEs play in schizophrenia?
A translocation disrupting PDE4B co-segregates with schizophrenia in a Scottish family. Millar (2000) in "Disruption of two novel genes by a translocation co-segregating with schizophrenia" reports a maximum LOD score of 6.0, implicating PDE4B in cAMP dysregulation. PDE4 inhibitors are explored as therapeutics based on this genetic link.
How are PDEs targeted therapeutically?
PDE inhibitors selectively block isoforms to elevate cyclic nucleotides for disease treatment. Bender and Beavo (2006) in "Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use" covers applications from cardiac regulation to neurodegeneration. Examples include PDE5 inhibitors for vascular diseases and PDE4 antagonists for inflammation.
What is compartmentalized PDE signaling?
PDEs localize to specific cellular compartments to shape local cAMP gradients. Conti and Beavo (2007) in "Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling" notes that isoform anchoring proteins enable this precision. It underlies isoform-specific functions in signaling pathways.
Open Research Questions
- ? How do specific PDE isoform interactions with anchoring proteins dictate compartmentalized cAMP signaling outcomes?
- ? What are the precise genetic mechanisms linking PDE4B disruptions to schizophrenia susceptibility?
- ? How can isoform-selective PDE inhibitors be optimized for cardiac function without off-target effects?
- ? What roles do PDEs play in integrating cAMP signals with Rap1 and MAP kinase pathways in neuronal development?
Recent Trends
The field encompasses 20,502 works with sustained interest in PDE isoform regulation and inhibitors, as foundational papers like Beavo with 1777 citations remain highly influential.
1995No growth rate data or recent preprints/news available indicate stable foundational research focus.
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