Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide

• Published in: Frontiers in neuroscience Vol. 13; p. 837
• Main Authors: Harms, John F, Menniti, Frank S, Schmidt, Christopher J
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 23.08.2019; Frontiers Media S.A
• Subjects: Attention; brain; Brain research; cGMP; Clinical trials; Cognitive ability; Cyclic GMP; Enzymes; Guanylate cyclase; Localization; Mental disorders; Neuroscience; Nitric oxide; Nitric-oxide synthase; PDE9A; Peptides; Phosphodiesterase; phosphodiesterase inhibitor; R&D; Research & development; Schizophrenia; Social research; Therapeutic applications; United States > US; nitric oxide; phosphodiesterase inhibitor; cGMP; nitric oxide synthase; brain; PDE9A; cognitive disorders
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2019.00837

PDE9A is a cGMP-specific phosphodiesterase expressed in neurons throughout the brain that has attracted attention as a therapeutic target to treat cognitive disorders. Indeed, PDE9A inhibitors are under evaluation in clinical trials as a treatment for Alzheimer's disease and schizophrenia. However, little is known about the cGMP signaling cascades regulated by PDE9A. Canonical cGMP signaling in brain follows the activation of neuronal nitric oxide synthase (nNOS) and the generation of nitric oxide, which activates soluble guanylyl cyclase and cGMP synthesis. However, we show that in mice, PDE9A regulates a pool of cGMP that is independent of nNOS, specifically, and nitric oxide signaling in general. This PDE9A-regulated cGMP pool appears to be highly compartmentalized and independent of cGMP pools regulated by several PDEs. These findings provide a new foundation for study of the upstream and downstream signaling elements regulated by PDE9A and its potential as a therapeutic target for brain disease.