ArticleBiophysical journal2017
Channeling of cAMP in PDE-PKA Complexes Promotes Signal Adaptation.
Article in Biophysical journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- Phosphodiesterase 8 regulation of excitation-contraction coupling as a target for cardiovascular disease: is it my turn now?American journal of physiology. Heart and circulatory physiology · 2026Review
- Conformational Dynamics and Allostery in the cAMP-Protein Kinase A Signalosome.Advances in experimental medicine and biology · 2026Review
- Recurrent Acrodysostosis-Related PKA RIα Mutant Reveals a Novel Mechanism of Aberrant PKA Deactivation.Journal of molecular biology · 2025Article
- Design principles of ciliary signaling.Journal of cell science · 2025Review
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Structural and functional characterization of Aedes aegypti pupal cuticle protein that controls dengue virus infection.Protein science : a publication of the Protein Society · 2023Article
- Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Coffee and cardiac arrhythmias: Up-date review of the literature and clinical studies.Cardiology journal · 2023Review
- Impaired cAMP processivity by phosphodiesterase-protein kinase A complexes in acrodysostosis.Frontiers in molecular biosciences · 2023Article
- Article
- 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
- Bridging protein structure, dynamics, and function using hydrogen/deuterium-exchange mass spectrometry.Protein science : a publication of the Protein Society · 2020Review
- Absolute proteomic quantification reveals design principles of sperm flagellar chemosensation.The EMBO journal · 2020Article
- Computational Modeling Reveals Frequency Modulation of Calcium-cAMP/PKA Pathway in Dendritic Spines.Biophysical journal · 2019Article
- Mitochondrial sub-cellular localization of cAMP-specific phosphodiesterase 8A in ovarian follicular cells.Scientific reports · 2019Article
- Hydrogen-deuterium exchange mass spectrometry reveals folding and allostery in protein-protein interactions.Methods (San Diego, Calif.) · 2018Review
- Novel Dual Mitochondrial and CD44 Receptor Targeting Nanoparticles for Redox Stimuli-Triggered Release.Nanoscale research letters · 2018Article
- "Riddle Me This": Substrate Channeling Solves the Paradigms of cAMP-Dependent Activation of PKA.Biophysical journal · 2017Article
- Osthole-Mediated Inhibition of Neurotoxicity Induced by Ropivacaine via Amplification of the Cyclic Adenosine Monophosphate Signaling Pathway.Dose-response : a publication of International Hormesis SocietyArticle
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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
Spatiotemporal control of the cAMP signaling pathway is governed by both hormonal stimulation of cAMP generation by adenylyl cyclases (activation phase) and cAMP hydrolysis by phosphodiesterases (PDEs) (termination phase). The termination phase is initiated by PDEs actively targeting the protein kinase A (PKA) R-subunit through formation of a PDE-PKAR-cyclic adenosine monophosphate (cAMP) complex (the termination complex). Our results using PDE8 as a model PDE, reveal that PDEs mediate active hydrolysis of cAMP bound to its receptor RIα by enhancing the enzymatic activity. This accelerated cAMP turnover occurs via formation of a stable PDE8-RIα complex, where the protein-protein interface forms peripheral contacts and the central ligand cements this ternary interaction. The basis for enhanced catalysis is active translocation of cAMP from its binding site on RIα to the hydrolysis site on PDE8 through direct "channeling." Our results reveal cAMP channeling in the PDE8-RIα complex and a molecular description of how this channel facilitates processive hydrolysis of unbound cAMP. Thus, unbound cAMP maintains the PDE8-RIα complex while being hydrolyzed, revealing an undiscovered mode for amplification of PKA activity by cAMP-mediated sequestration of the R-subunit by PDEs. This novel regulatory mode explains the paradox of cAMP signal amplification by accelerated PDE-mediated cAMP turnover. This highlights how target effector proteins of small-molecule ligands can promote enzyme-mediated ligand hydrolysis by scaffolding effects. Enhanced activity of the PDE8-RIα complex facilitates robust desensitization, allowing the cell to respond to dynamic levels of cAMP rather than steady-state levels. The PDE8-RIα complex represents a new class of PDE-based complexes for specific drug discovery targeting the cAMP signaling pathway.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.