Cyclic nucleotide phosphodiesterase 1 (PDE1)

Cyclic nucleotide phosphodiesterase 1 (PDE1), also known as Ca2+/calmodulin-dependent phosphodiesterase, is a family of enzymes that uniquely integrate calcium and cyclic nucleotide signaling (1.3.1, 1.3.2). PDE1 is the only phosphodiesterase family activated by the Ca2+/calmodulin complex, making its activity dependent on intracellular calcium elevations (1.3.1). The family comprises three isoforms—PDE1A, PDE1B, and PDE1C—which are widely distributed in the central nervous system, myocardium, and vascular smooth muscle (1.3.2, 1.3.3). These enzymes hydrolyze both cAMP and cGMP, thereby regulating critical processes such as neuronal plasticity, cardiac remodeling, and vascular tone (1.3.3, 1.4.4). PDE1 is a significant therapeutic target for neurodegenerative diseases like Alzheimer's and Parkinson's, as well as cardiovascular conditions including heart failure and pulmonary arterial hypertension (1.3.2, 1.3.3). Selective PDE1 inhibitors, such as lenrispodun (ITI-214), are being developed to enhance cognitive function and improve cardiovascular outcomes by sustaining cyclic nucleotide signaling (1.2.2, 1.3.3). Current research also explores the role of PDE1 in inflammatory responses and cancer progression (1.2.2, 1.3.2).

Other names

Ca2+/calmodulin-dependent phosphodiesteraseCaMPDECalcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterasePDE1 family

Inhibition of the catalytic domain of PDE1 isoforms, preventing the hydrolysis of cAMP and cGMP. This leads to the accumulation of these second messengers, which activate protein kinases (PKA and PKG) and modulate downstream signaling involved in neuronal plasticity, vascular relaxation, and inflammation (1.3.3, 1.3.4).