Phosphodiesterases

Phosphodiesterases (PDEs) are a family of enzymes that catalyze the hydrolysis of cyclic nucleotides cAMP and cGMP, regulating intracellular signaling. They terminate or reshape signals by lowering cyclic nucleotide levels, thereby modulating activity of protein kinase A (PKA), protein kinase G (PKG), and cyclic-nucleotide gated channels.

Mammals express 11 PDE gene families (PDE1–PDE11), with multiple isoforms from alternative splicing; substrates and tissue distribution vary. Some PDEs preferentially hydrolyze cAMP (e.g., PDE4, PDE7, PDE8), some are cGMP-specific (PDE5, PDE6, PDE9), and others are dual-specific (PDE1, PDE2, PDE3, PDE10). Many possess regulatory domains such as calmodulin-binding domains (PDE1), or GAF domains that bind cyclic nucleotides or ligands, and a conserved catalytic domain containing two metal ions required for hydrolysis.

PDEs influence cardiovascular, nervous, metabolic, and sensory functions; dysregulation is implicated in disease. Clinically, selective PDE inhibitors are used: PDE5 inhibitors (sildenafil, tadalafil) for erectile dysfunction and pulmonary hypertension; PDE4 inhibitors (roflumilast) for COPD and inflammatory conditions; PDE3 inhibitors (milrinone) as inotropic agents for heart failure; ongoing research for other isoforms.