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Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide
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,...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716477/ https://www.ncbi.nlm.nih.gov/pubmed/31507355 http://dx.doi.org/10.3389/fnins.2019.00837 |
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author | Harms, John F. Menniti, Frank S. Schmidt, Christopher J. |
author_facet | Harms, John F. Menniti, Frank S. Schmidt, Christopher J. |
author_sort | Harms, John F. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6716477 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-67164772019-09-10 Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide Harms, John F. Menniti, Frank S. Schmidt, Christopher J. Front Neurosci Neuroscience 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. Frontiers Media S.A. 2019-08-23 /pmc/articles/PMC6716477/ /pubmed/31507355 http://dx.doi.org/10.3389/fnins.2019.00837 Text en Copyright © 2019 Harms, Menniti and Schmidt. http://creativecommons.org/licenses/by/4.0/ 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. |
spellingShingle | Neuroscience Harms, John F. Menniti, Frank S. Schmidt, Christopher J. Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide |
title | Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide |
title_full | Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide |
title_fullStr | Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide |
title_full_unstemmed | Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide |
title_short | Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide |
title_sort | phosphodiesterase 9a in brain regulates cgmp signaling independent of nitric-oxide |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716477/ https://www.ncbi.nlm.nih.gov/pubmed/31507355 http://dx.doi.org/10.3389/fnins.2019.00837 |
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