ArticleMolecular & cellular proteomics : MCP2011
Phosphodiesterases catalyze hydrolysis of cAMP-bound to regulatory subunit of protein kinase A and mediate signal termination.
Article in Molecular & cellular proteomics : MCP, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
- Conformational Dynamics and Allostery in the cAMP-Protein Kinase A Signalosome.Advances in experimental medicine and biology · 2026Review
- GPCR signaling via cAMP nanodomains.The Biochemical journal · 2025Review
- A Comprehensive Review of Mammalian Pigmentation: Paving the Way for Innovative Hair Colour-Changing Cosmetics.Biology · 2023Review
- Impaired cAMP processivity by phosphodiesterase-protein kinase A complexes in acrodysostosis.Frontiers in molecular biosciences · 2023Article
- DNA methylation may affect beef tenderness through signal transduction in Bos indicus.Epigenetics & chromatin · 2022Article
- Development of Phosphodiesterase-Protein-Kinase Complexes as Novel Targets for Discovery of Inhibitors with Enhanced Specificity.International journal of molecular sciences · 2021Article
- Synergistic Allostery in Multiligand-Protein Interactions.Biophysical journal · 2020Article
- Hydrogen-deuterium exchange mass spectrometry reveals folding and allostery in protein-protein interactions.Methods (San Diego, Calif.) · 2018Review
- PKA-RII subunit phosphorylation precedes activation by cAMP and regulates activity termination.The Journal of cell biology · 2018Article
- α-Viniferin Improves Facial Hyperpigmentation via Accelerating Feedback Termination of cAMP/PKA-Signaled Phosphorylation Circuit in Facultative Melanogenesis.Theranostics · 2018Article
- PTHrP(12-48) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2017Article
- Channeling of cAMP in PDE-PKA Complexes Promotes Signal Adaptation.Biophysical journal · 2017Article
- Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair.International journal of molecular sciences · 2017Review
- β-subunit myristoylation functions as an energy sensor by modulating the dynamics of AMP-activated Protein Kinase.Scientific reports · 2016Article
- Unidirectional allostery in the regulatory subunit RIα facilitates efficient deactivation of protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations.Mitochondrion · 2016Article
- Parallel Allostery by cAMP and PDE Coordinates Activation and Termination Phases in cAMP Signaling.Biophysical journal · 2015Article
- Spatiotemporal stability of neonatal rat cardiomyocyte monolayers spontaneous activity is dependent on the culture substrate.PloS one · 2015Article
- Using Markov state models to develop a mechanistic understanding of protein kinase A regulatory subunit RIα activation in response to cAMP binding.The Journal of biological chemistry · 2014Article
- Signaling at crossroads: the dialogue between PDEs and PKA is spoken in multiple languages.Biophysical journal · 2014Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although extensive structural and biochemical studies have provided molecular insights into the mechanism of cAMP-dependent activation of protein kinase A (PKA), little is known about signal termination and the role of phosphodiesterases (PDEs) in regulatory feedback. In this study we describe a novel mode of protein kinase A-anchoring protein (AKAP)-independent feedback regulation between a specific PDE, RegA and the PKA regulatory (RIα) subunit, where RIα functions as an activator of PDE catalysis. Our results indicate that RegA, in addition to its well-known role as a PDE for bulk cAMP in solution, is also capable of hydrolyzing cAMP-bound to RIα. Furthermore our results indicate that binding of RIα activates PDE catalysis several fold demonstrating a dual function of RIα, both as an inhibitor of the PKA catalytic (C) subunit and as an activator for PDEs. Deletion mutagenesis has localized the sites of interaction to one of the cAMP-binding domains of RIα and the catalytic PDE domain of RegA whereas amide hydrogen/deuterium exchange mass spectrometry has revealed that the cAMP-binding site (phosphate binding cassette) along with proximal regions important for relaying allosteric changes mediated by cAMP, are important for interactions with the PDE catalytic domain of RegA. These sites of interactions together with measurements of cAMP dissociation rates demonstrate that binding of RegA facilitates dissociation of cAMP followed by hydrolysis of the released cAMP to 5'AMP. cAMP-free RIα generated as an end product remains bound to RegA. The PKA C-subunit then displaces RegA and reassociates with cAMP-free RIα to regenerate the inactive PKA holoenzyme thereby completing the termination step of cAMP signaling. These results reveal a novel mode of regulatory feedback between PDEs and RIα that has important consequences for PKA regulation and cAMP signal termination.
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