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Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

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Item Type:Article
Title:Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases
Creators Name:Omar, F. and Findlay, J.E. and Carfray, G. and Allcock, R.W. and Jiang, Z. and Moore, C. and Muir, A.L. and Lannoy, M. and Fertig, B.A. and Mai, D. and Day, J.P. and Bolger, G. and Baillie, G.S. and Schwiebert, E. and Klussmann, E. and Pyne, N.J. and Ong, A.C.M. and Bowers, K. and Adam, J.M. and Adams, D.R. and Houslay, M.D. and Henderson, D.J.P.
Abstract:Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased V(max) with unchanged K(m)), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.
Keywords:PDE4, PDE4 Activator, Cyclic AMP, ADPKD, Phosphodiesterase, Animals, Dogs
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:13320-13329
Date:2 July 2019
Official Publication:https://doi.org/10.1073/pnas.1822113116
PubMed:View item in PubMed

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