ArticleCells2025
The Molecular Mechanism of PDE1 Regulation.
Article in Cells, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review).International journal of molecular medicine · 2026Review
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4 authors.
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Abstract
The phosphodiesterase 1 genes PDE1A, PDE1B, and PDE1C encode calcium-regulated cyclic nucleotide phosphodiesterases that mediate the interplay between calcium and cyclic nucleotide signaling in the brain, heart, and vasculature. While an inhibitory domain and a calmodulin-binding domain have been identified in PDE1, the mechanism of regulation is not understood. In this study, we investigated the regulatory mechanism through a series of experiments. The experimental data, supported by AlphaFold structure predictions, consistently point to the following model of PDE1 regulation: In the absence of calcium, the inhibitory domain of PDE1 binds to and blocks the catalytic site via molecular interactions that closely resemble those observed in autoinhibited PDE4. Upon calcium/calmodulin binding to PDE1's calmodulin-binding domain, steric constraints prevent the inhibitory domain from reaching the catalytic site, thereby activating PDE1. Understanding this mode of PDE1 regulation may open new avenues for pharmacological intervention. Moreover, it establishes PDE1 and PDE4 as a second mechanistic class of phosphodiesterase regulation in addition to the GAF-domain-mediated regulation known to control the activity of several other PDEs.
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