cGMP-inhibited 3',5'-cyclic phosphodiesterase 3 (PDE3)

cGMP-inhibited 3',5'-cyclic phosphodiesterase 3 (PDE3) is a family of dual-specificity enzymes, primarily comprising the isoforms PDE3A and PDE3B, that regulate intracellular levels of cAMP and cGMP (UniProt Q14432, Q13370). It is uniquely characterized by its high affinity for cAMP hydrolysis, which is competitively inhibited by cGMP, allowing for critical crosstalk between these two second messenger pathways (PubMed: 8695850). PDE3 is highly expressed in tissues such as the myocardium, vascular smooth muscle, platelets, and adipocytes, where it controls physiological processes like cardiac contractility, vascular tone, and platelet aggregation. In clinical therapy, PDE3 is a target for acute heart failure and intermittent claudication; drugs such as milrinone and cilostazol inhibit the enzyme to elevate cAMP, thereby enhancing myocardial contractility and blood flow (PMC: PMC3114972). However, long-term therapeutic use of PDE3 inhibitors is restricted by significant safety concerns, including a risk of life-threatening arrhythmias and increased mortality in patients with chronic heart failure (PMC: PMC6685040). Additionally, PDE3 plays roles in insulin-mediated metabolic regulation, oocyte maturation, and inflammatory responses, reflecting its broad influence on cellular signaling (PMID: 21393242).

Other names

PDE3CGI-PDECyclic GMP-inhibited phosphodiesteraseType III phosphodiesteraseType 3 phosphodiesterasecGMP-inhibited cAMP phosphodiesterase

Drugs targeting PDE3 act as competitive inhibitors of the catalytic domain, preventing the hydrolysis of cAMP and cGMP. This leads to increased intracellular concentrations of cAMP, which subsequently activates protein kinase A (PKA) and downstream effectors, such as L-type calcium channels in the heart to increase contractility or inhibitory pathways in platelets to prevent aggregation (PMID: 1315035, PubMed Central: PMC6685040).