Short PDE4 Isoforms as Drug Targets in Disease
The second messenger, cyclic adenosine monophosphate (cAMP), is a master regulator of signal transduction that maintains cell homeostasis. A fine balance between cAMP synthesis by adenylyl cyclase and degradation by phosphodiesterases (PDEs) underpins receptor-specific responses. As multiple recepto...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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IMR Press
2023-07-01
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| Series: | Frontiers in Bioscience-Landmark |
| Subjects: | |
| Online Access: | https://www.imrpress.com/journal/FBL/28/7/10.31083/j.fbl2807133 |
| _version_ | 1797767938251423744 |
|---|---|
| author | Elka Kyurkchieva George S. Baillie |
| author_facet | Elka Kyurkchieva George S. Baillie |
| author_sort | Elka Kyurkchieva |
| collection | DOAJ |
| description | The second messenger, cyclic adenosine monophosphate (cAMP), is a master regulator of signal transduction that maintains cell homeostasis. A fine balance between cAMP synthesis by adenylyl cyclase and degradation by phosphodiesterases (PDEs) underpins receptor-specific responses. As multiple receptors rely on cAMP for signaling, PDEs shape three-dimensional, localized gradients of the cyclic nucleotide to drive appropriate signaling cascades. Of the 11 PDE families, PDE4, which comprises long, short, and supershort isoforms and a dead-short isoform, is of great interest due to its implication in disease. Aberrant PDE4 expression and post-translational modifications are hallmarks of several clinical indications for which curative treatment is not yet available. While some PDE4-specific small molecule inhibitors directed against the active site are approved for clinical use, they are limited by severe side effects owing to the high degree of conservation of the catalytic domain between over 20 unique isoforms. Some attempts to use the different modular structure that exists between long and shorter isoforms are now bearing success. However, these inhibitors are exclusively aimed at PDE4 long isoforms, which have been the focus of the majority of research in this area. Here, we have summarised literature on the lesser-studied short PDE4 isoforms and provide a record of the discovery, regulation, and disease relevance of this class of enzymes that represent an untapped target for specific inhibition in the future. |
| first_indexed | 2024-03-12T20:47:14Z |
| format | Article |
| id | doaj.art-8d7ca209cf6940caa3f08b1381a5dadd |
| institution | Directory Open Access Journal |
| issn | 2768-6701 |
| language | English |
| last_indexed | 2024-03-12T20:47:14Z |
| publishDate | 2023-07-01 |
| publisher | IMR Press |
| record_format | Article |
| series | Frontiers in Bioscience-Landmark |
| spelling | doaj.art-8d7ca209cf6940caa3f08b1381a5dadd2023-08-01T07:41:59ZengIMR PressFrontiers in Bioscience-Landmark2768-67012023-07-0128713310.31083/j.fbl2807133S2768-6701(23)00921-8Short PDE4 Isoforms as Drug Targets in DiseaseElka Kyurkchieva0George S. Baillie1School of Cardiovascular & Metabolic Health, University of Glasgow, G12 8QQ Glasgow, UKSchool of Cardiovascular & Metabolic Health, University of Glasgow, G12 8QQ Glasgow, UKThe second messenger, cyclic adenosine monophosphate (cAMP), is a master regulator of signal transduction that maintains cell homeostasis. A fine balance between cAMP synthesis by adenylyl cyclase and degradation by phosphodiesterases (PDEs) underpins receptor-specific responses. As multiple receptors rely on cAMP for signaling, PDEs shape three-dimensional, localized gradients of the cyclic nucleotide to drive appropriate signaling cascades. Of the 11 PDE families, PDE4, which comprises long, short, and supershort isoforms and a dead-short isoform, is of great interest due to its implication in disease. Aberrant PDE4 expression and post-translational modifications are hallmarks of several clinical indications for which curative treatment is not yet available. While some PDE4-specific small molecule inhibitors directed against the active site are approved for clinical use, they are limited by severe side effects owing to the high degree of conservation of the catalytic domain between over 20 unique isoforms. Some attempts to use the different modular structure that exists between long and shorter isoforms are now bearing success. However, these inhibitors are exclusively aimed at PDE4 long isoforms, which have been the focus of the majority of research in this area. Here, we have summarised literature on the lesser-studied short PDE4 isoforms and provide a record of the discovery, regulation, and disease relevance of this class of enzymes that represent an untapped target for specific inhibition in the future.https://www.imrpress.com/journal/FBL/28/7/10.31083/j.fbl2807133phosphodiesterasecyclic ampshort isoforminflammationmultiple sclerosisalzheimer's diseasetraumatic brain injurycancerchronic obstructive pulmonary diseasedrug target |
| spellingShingle | Elka Kyurkchieva George S. Baillie Short PDE4 Isoforms as Drug Targets in Disease Frontiers in Bioscience-Landmark phosphodiesterase cyclic amp short isoform inflammation multiple sclerosis alzheimer's disease traumatic brain injury cancer chronic obstructive pulmonary disease drug target |
| title | Short PDE4 Isoforms as Drug Targets in Disease |
| title_full | Short PDE4 Isoforms as Drug Targets in Disease |
| title_fullStr | Short PDE4 Isoforms as Drug Targets in Disease |
| title_full_unstemmed | Short PDE4 Isoforms as Drug Targets in Disease |
| title_short | Short PDE4 Isoforms as Drug Targets in Disease |
| title_sort | short pde4 isoforms as drug targets in disease |
| topic | phosphodiesterase cyclic amp short isoform inflammation multiple sclerosis alzheimer's disease traumatic brain injury cancer chronic obstructive pulmonary disease drug target |
| url | https://www.imrpress.com/journal/FBL/28/7/10.31083/j.fbl2807133 |
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