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

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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.

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          Most cited references59

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          Localization of nitric oxide synthase indicating a neural role for nitric oxide.

          Nitric oxide (NO), apparently identical to endothelium-derived relaxing factor in blood vessels, is also formed by cytotoxic macrophages, in adrenal gland and in brain tissue, where it mediates the stimulation by glutamate of cyclic GMP formation in the cerebellum. Stimulation of intestinal or anococcygeal nerves liberates NO, and the resultant muscle relaxation is blocked by arginine derivatives that inhibit NO synthesis. It is, however, unclear whether in brain or intestine, NO released following nerve stimulation is formed in neurons, glia, fibroblasts, muscle or blood cells, all of which occur in proximity to neurons and so could account for effects of nerve stimulation on cGMP and muscle tone. We have now localized NO synthase protein immunohistochemically in the rat using antisera to the purified enzyme. We demonstrate NO synthase in the brain to be exclusively associated with discrete neuronal populations. NO synthase is also concentrated in the neural innervation of the posterior pituitary, in autonomic nerve fibres in the retina, in cell bodies and nerve fibres in the myenteric plexus of the intestine, in adrenal medulla, and in vascular endothelial cells. These prominent neural localizations provide the first conclusive evidence for a strong association of NO with neurons.
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            Nitric oxide signaling in the central nervous system.

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              Phosphodiesterase 9A Controls Nitric-oxide Independent cGMP and Hypertrophic Heart Disease

              Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric oxide (NO) and natriuretic peptide (NP) coupled signaling, stimulating phosphorylation changes by protein kinase G (PKG). Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease 1,2 . However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation 3 . Furthermore, though PDE5A regulates NO-generated cGMP 4,5 , NO-signaling is often depressed by heart disease 6 . PDEs controlling NP-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A 7,8 is expressed in mammalian heart including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates NP rather than NO-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neuro-hormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of NO-synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phospho-proteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signaling independent of the NO-pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                23 August 2019
                2019
                : 13
                : 837
                Affiliations
                [1] 1Internal Medicine Research Unit, Pfizer Global Research and Development , Cambridge, MA, United States
                [2] 2George & Anne Ryan Institute for Neuroscience, The University of Rhode Island , Kingston, RI, United States
                [3] 3Pfizer Innovation and Research Lab Unit, Pfizer Global Research and Development , Cambridge, MA, United States
                Author notes

                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

                *Correspondence: Christopher J. Schmidt, cjschmidt.brm@ 123456gmail.com

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2019.00837
                6716477
                31507355
                d5c73967-966e-479e-83f5-eba745627933
                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.

                History
                : 06 May 2019
                : 26 July 2019
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 60, Pages: 12, Words: 0
                Categories
                Neuroscience
                Original Research

                Neurosciences
                cgmp,pde9a,phosphodiesterase inhibitor,nitric oxide,nitric oxide synthase,brain,cognitive disorders

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