Understanding the complex inner workings of the heart is a crucial step towards developing effective treatments for cardiovascular disease. One important aspect is the way in which cells communicate with each other through the signalling molecule cAMP. This molecule is known to operate through compartmentalisation into tiny regions, or nanodomains, each with its own specific role in cell function. Each of these nanodomains is regulated by one, or a combination of, specific cAMP-hydrolysing enzymes called phosphodiesterases, which controls its function.
Research has linked disruption of these nanodomains to heart disease, demonstrating it is vitally important that cAMP functions correctly at the subcellular level. However, this research has largely focused on a small number of predictable subcellular locations, leaving much of the system unexplored. The detailed inner workings of the cAMP nanodomain organisation have therefore remained elusive.
A new study from the Zaccolo group in Department of Physiology, Anatomy and Genetics (DPAG) used an unbiased approach to uncover previously unseen cAMP nanodomains in cardiac myocytes. The team has conducted an integrated phospho-interactomics analysis of specific phosphodiesterase isoforms to unveil several novel cAMP nanodomains. One of these newly identified nanodomains is located within the nucleus and regulates cardiac myocyte hypertrophy, a process involved in the cardiac remodelling associated with heart failure. Researchers found that a specific type of phosphodiesterase called PDE3A2 is responsible for regulating this nanodomain through PKA-dependent regulation of HDAC1 activity. By inhibiting PDE3A2, researchers were able to trigger hypertrophy in both rodent and human heart cells.