Year: 2026
Type: preprint
Abstract: Spatial compartmentalisation enables cyclic AMP (cAMP) to regulate distinct cellular functions, yet selectively targeting disease-associated signalling remains challenging. Phosphodiesterases constrain local cAMP responses, but conventional inhibitors offer limited isoform selectivity. Here we investigate whether targeted degradation of long phosphodiesterase-4D (PDE4D) isoforms can suppress pathological growth while preserving contractile function. Using adult rat and human ventricular cardiomyocytes and human myocardial slices, we show that the proteolysis-targeting chimera KTX-184 enhances compartmentalised cAMP signalling and attenuates hypertrophic remodelling. In rat cardiomyocytes, KTX-184 increases β-adrenergic cAMP responses in the cytosol and at the plasma membrane, including T-tubule and crest regions, and enhances nuclear protein kinase A activity. In contrast, phospholamban- and ryanodine receptor-associated cAMP nanodomains, calcium transients and sarcomere shortening remain unchanged. KTX-184 prevents angiotensin II-induced hypertrophic remodelling, preserves T-tubule organisation and normalises hypertrophic marker expression. In human cardiomyocytes, it increases cytosolic cAMP responses and prevents overload-induced hypertrophy in myocardial slices. These findings identify long PDE4D isoforms as targets for spatially selective modulation of cAMP signalling and support targeted degradation as an approach to suppress cardiac hypertrophy without increasing contractility.
Authors: Aleksandra Judina, Zhiyao Shi, Jiarong Fu, Ivan Sherstnev, Veronika Boichenko, Jiayue Ling, Madihah Hussain, Alina Zorn, Yuan Yan Sin, Houcheng Wang, Ao Li, Sasha Korogodski, Eduardo Torres, David Stirling, Kyle Chan, Cathy Swindlehurst, Iyobel Kibread, Iain Black, Stuart Nicklin, George S. Baillie, Julia Gorelik
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225100316