PDE1

Phosphodiesterase PDE1 encodes Ca²⁺/calmodulin-regulated cyclic nucleotide phosphodiesterases that connect Ca²⁺ signaling with cAMP and cGMP degradation in the brain, heart, and vasculature^[1]. Mechanistically, Ca²⁺/calmodulin binding activates PDE1 by preventing an inhibitory domain from blocking the catalytic site, thereby controlling cyclic nucleotide signaling amplitude and compartmentation^[1]. In cardiovascular disease models, PDE1A is induced in activated cardiac myofibroblasts after Ang II or TGF-β stimulation and regulates extracellular matrix synthesis through cAMP-Epac-Rap1 and cGMP-PKG signaling^[2]. In human arterial smooth muscle cells, PDE1C is highly expressed in proliferating primary cultures and severe atherosclerotic lesions, but not in quiescent intact human aorta^[3]. Compared with related isoforms, human, monkey, and rat smooth muscle cells show different PDE1 patterns, with human cells expressing PDE1C, monkey cells expressing PDE1B, and rat cells expressing PDE1A^[3]. In sperm models, PDE1A localizes to the equatorial sperm head and flagellum, and mouse PDE1A_v7 is a major mature sperm PDE1A variant regulating cyclic nucleotide hydrolysis^[4][5]. For experimental applications, KS-505a selectively inhibits Ca²⁺/calmodulin-activated PDE1 isoenzymes and distinguishes subfamily members in brain-region models^[6].