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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.00837

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

  • 1Pfizer (United States), United States
  • 2The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, United States
  • 3Pfizer Innovation and Research Lab, United States

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.

Keywords: cGMP, PDE9A, phosphodiesterase inhibitor, Nitric Oxide, Nitric Oxide Synthase, Brain, Cognitive Disorders

Received: 06 May 2019; Accepted: 26 Jul 2019.

Edited by:

Arjan Blokland, Maastricht University, Netherlands

Reviewed by:

Mariela F. Perez, Universidad Nacional de Córdoba, Argentina
Iria G. Dopeso-Reyes, UMR5535 Institut de Génétique Moléculaire de Montpellier (IGMM), France  

Copyright: © 2019 Harms, Menniti and Schmidt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Christopher J. Schmidt, Pfizer Innovation and Research Lab, Cambridge, United States,