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. Howe...

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Published inFrontiers in neuroscience Vol. 13; p. 837
Main Authors Harms, John F, Menniti, Frank S, Schmidt, Christopher J
Format Journal Article
LanguageEnglish
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
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Abstract 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.
AbstractList 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.
Author Menniti, Frank S
Schmidt, Christopher J
Harms, John F
AuthorAffiliation 3 Pfizer Innovation and Research Lab Unit, Pfizer Global Research and Development , Cambridge, MA , United States
2 George & Anne Ryan Institute for Neuroscience, The University of Rhode Island , Kingston, RI , United States
1 Internal Medicine Research Unit, Pfizer Global Research and Development , Cambridge, MA , United States
AuthorAffiliation_xml – name: 3 Pfizer Innovation and Research Lab Unit, Pfizer Global Research and Development , Cambridge, MA , United States
– name: 1 Internal Medicine Research Unit, Pfizer Global Research and Development , Cambridge, MA , United States
– name: 2 George & Anne Ryan Institute for Neuroscience, The University of Rhode Island , Kingston, RI , United States
Author_xml – sequence: 1
  givenname: John F
  surname: Harms
  fullname: Harms, John F
  organization: Internal Medicine Research Unit, Pfizer Global Research and Development, Cambridge, MA, United States
– sequence: 2
  givenname: Frank S
  surname: Menniti
  fullname: Menniti, Frank S
  organization: George & Anne Ryan Institute for Neuroscience, The University of Rhode Island, Kingston, RI, United States
– sequence: 3
  givenname: Christopher J
  surname: Schmidt
  fullname: Schmidt, Christopher J
  organization: Pfizer Innovation and Research Lab Unit, Pfizer Global Research and Development, Cambridge, MA, United States
BackLink https://www.ncbi.nlm.nih.gov/pubmed/31507355$$D View this record in MEDLINE/PubMed
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Copyright © 2019 Harms, Menniti and Schmidt. 2019 Harms, Menniti and Schmidt
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Keywords nitric oxide
phosphodiesterase inhibitor
cGMP
nitric oxide synthase
brain
PDE9A
cognitive disorders
Language English
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This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience
Edited by: Arjan Blokland, Maastricht University, Netherlands
Reviewed by: Mariela Fernanda Perez, Universidad Nacional de Córdoba, Argentina; Iria Gonzalez Dopeso-Reyes, UMR 5535 Institut de Génétique Moléculaire de Montpellier (IGMM), France
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Snippet PDE9A is a cGMP-specific phosphodiesterase expressed in neurons throughout the brain that has attracted attention as a therapeutic target to treat cognitive...
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SubjectTerms 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
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Title Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide
URI https://www.ncbi.nlm.nih.gov/pubmed/31507355
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https://pubmed.ncbi.nlm.nih.gov/PMC6716477
https://doaj.org/article/dd9e962be81043f1945350d390769c0a
Volume 13
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