Short PDE4 isoforms as drug targets in disease

Kyurkchieva, E. and Baillie, G. S. (2023) Short PDE4 isoforms as drug targets in disease. Frontiers in Bioscience: Landmark, 28(7), 133. (doi: 10.31083/j.fbl2807133) (PMID:37525918)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kyurkchieva, Ms Elka and Baillie, Professor George
• Authors: Kyurkchieva, E., and Baillie, G. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Frontiers in Bioscience: Landmark
• Publisher: IMR Press
• ISSN: 2768-6701
• ISSN (Online): 2768-6698
• Published Online: 04 July 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Frontiers in Bioscience: Landmark 28(7): 133
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
301414		Targeting PDE3/4 to allow regulation of cardiac calcium homeostasis in disease	George Baillie	British Heart Foundation (BHF)	PG/17/26/32881	CAMS - Cardiovascular Science