Phosphodiesterase

Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze the phosphodiester bond in cyclic nucleotides, thereby regulating the levels of signaling molecules such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). By degrading these messengers, PDEs terminate or modulate signal transduction pathways that control diverse cellular processes.

In humans, PDEs comprise 11 families (PDE1 through PDE11), encoded by multiple genes and expressed in a tissue-specific manner. Each family has distinct substrate preferences: some are selective for cAMP, others for cGMP, and several display dual specificity. For example, PDE1 is Ca2+/calmodulin-stimulated; PDE3 hydrolyzes both cAMP and cGMP and is inhibited by cGMP; PDE4 is specific for cAMP; PDE5 and PDE9 preferentially hydrolyze cGMP. Most PDEs require divalent metal ions, such as Mg2+ or Mn2+, for catalytic activity and contain regulatory domains that influence activity in response to cellular signals.

Physiologically, PDEs shape signaling in many tissues, including heart and vascular smooth muscle, platelets, brain, and retina. By controlling cyclic nucleotide concentrations, they influence processes such as cardiac contractility, vascular tone, neurotransmission, and vision.

Clinically, PDE inhibitors are used to elevate cAMP or cGMP levels for therapeutic benefit. Examples include PDE5 inhibitors (sildenafil, tadalafil) for erectile dysfunction and pulmonary hypertension; PDE3 inhibitors (cilostazol) for intermittent claudication; PDE4 inhibitors (apremilast, roflumilast) for inflammatory conditions and COPD. Side effects can include hypotension, headaches, and gastrointestinal symptoms, reflecting widespread roles of cyclic nucleotides.