Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 31 July 2024 | Viewed by 2369

Special Issue Editors


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Guest Editor
Department of Cell Biology, UConn Health, Farmington, CT, USA
Interests: cyclic nucleotide phosphodiesterases; PDEs; cAMP; cGMP; signal transduction; second messengers

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Guest Editor
Department of Immunology, UConn Health, Farmington, CT, USA
Interests: neuroinflammation; T cells; leukocyte migration; cAMP signaling; phosphodiesterases; immunotherapy; neurodegeneration

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Guest Editor
University of Maryland School of Medicine, Baltimore, MD, USA
Interests: 3’,5’-cyclic nucleotide phosphodiesterases (PDEs); learning and memory; social behavior; age-related cognitive decline; Alzheimer’s disease

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Guest Editor
Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA
Interests: liver injury; inflammation; fibrogenesis; cAMP signaling; phosphodiesterases; recent photo

Special Issue Information

Dear Colleagues,

In 1957, when Earl Sutherland and Ted Rall discovered cAMP as the first “second messenger” mediating the effects of hormones on liver and skeletal muscle, the field of signal transduction, the way in which cells communicate with each other and respond to external signals, was born. It is apparent now that many diseases result from something going wrong in these signal transduction processes, and correcting the spatial and temporal changes in cAMP levels in subcellular compartments back to normal can therapeutically treat these resultant diseases. An enzymatic activity, cAMP phosphodiesterase (PDE), capable of converting cAMP to 5’-AMP, which terminates the messenger function of cAMP, was reported at the time of its discovery. We now know that PDEs represent a superfamily of enzymes encoded by 21 different genes grouped into 11 gene families.  More than 100 different forms of PDE have now been identified, some of which are selectively located in different cell types and in different subcellular compartments. With this degree of complexity, by inhibiting or altering the expression of specific forms of PDE, we can change fundamental physiological processes in one cell type, without affecting others, which is the basis and goal of targeted therapies. To this end, efforts have been focused on which PDEs mediate which cell processes and on developing selective inhibitors of these PDEs to correct a wide variety of disease states. Drugs that target PDEs have now been approved for COPD, psoriasis, atopic dermatitis, erectile dysfunction, pulmonary hypertension, and heart failure. And this is only the tip of the iceberg, as they also show therapeutic benefits for a wide range of cancers, CNS disorders, autoimmune disorders, and metabolic disorders.

The aim of this Special Issue is to highlight recent advances in targeting PDEs for therapeutic benefit, and we would be delighted to have you join us in this by submitting your recent work.

Dr. Paul M. Epstein
Dr. Stefan Brocke
Dr. Michy P. Kelly
Dr. Leila Gobejishvili
Guest Editors

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Keywords

  • cyclic nucleotide phosphodiesterase
  • PDE
  • cAMP
  • cGMP
  • signal transduction

Published Papers (2 papers)

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Research

25 pages, 4396 KiB  
Article
Effects of the Phosphodiesterase 10A Inhibitor MR1916 on Alcohol Self-Administration and Striatal Gene Expression in Post-Chronic Intermittent Ethanol-Exposed Rats
by Luísa B. Bertotto, Dolly Lampson-Stixrud, Anushka Sinha, Nicki K. Rohani, Isabella Myer and Eric P. Zorrilla
Cells 2024, 13(4), 321; https://doi.org/10.3390/cells13040321 - 09 Feb 2024
Viewed by 713
Abstract
Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control [...] Read more.
Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats (n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers (Pde10a, Drd1, Drd2, Penk, and Tac1) and immediate-early genes (IEG) (Fos, Fosb, ΔFosb, and Egr1) in EtOH-naïve (n = 5–6/grp) and post-CIE (n = 6–8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1, Fos, and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking. Full article
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25 pages, 3813 KiB  
Article
The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme
by Irina Sbornova, Emilie van der Sande, Snezana Milosavljevic, Elvis Amurrio, Steven D. Burbano, Prosun K. Das, Helen H. Do, Janet L. Fisher, Porschderek Kargbo, Janvi Patel, Latarsha Porcher, Chris I. De Zeeuw, Magda A. Meester-Smoor, Beerend H. J. Winkelman, Caroline C. W. Klaver, Ana Pocivavsek and Michy P. Kelly
Cells 2023, 12(24), 2839; https://doi.org/10.3390/cells12242839 - 14 Dec 2023
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Abstract
Recently, a Y727C variant in the dual-specific 3′,5′-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined [...] Read more.
Recently, a Y727C variant in the dual-specific 3′,5′-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia. Full article
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