INT'L GUEST SPEAKER Professor Viacheslav Nikolaev, Universitätsklinikum Hamburg-Eppendorf (UKE) Institute of Experimental Cardiovascular Research: ‘Shining light on local cAMP signalling in cardiac disease’

Cyclic adenosine monophosphate (cAMP) regulates numerous physiological functions by acting in subcellular microdomains. Cardiac actions of cAMP include but are not limited to the modulation of contractility, pathological growth and remodelling. This is achieved at least in part, by local pools of cAMP formed around calcium handling proteins such as L-type calcium channels located in T-tubules or caveolin-rich membrane structures as well as calcium release and reuptake units found in sarcoplasmatic reticulum. Recently, we developed several differentially localised versions of a highly sensitive cytosolic cAMP Förster resonance energy transfer (FRET)-based biosensor Epac1-camps and expressed them in transgenic mice to study the regulation of local cAMP dynamics and their alterations in cardiac disease. Using these new tools and live cell imaging, we could uncover that cardiac hypertrophy and early heart failure are associated with relocation of the cGMP-regulated phosphodiesterases (PDEs) 2 and 3 between beta-adrenoceptor associated submembrane microdomains and between plasma membrane and sarcoplasmic reticulum. In addition, some cAMP-specific PDE4 isoforms were found to relocate between calcium release channels and the cytosol. This newly identified molecular mechanism may allow some functional compensation such as augmentation of catecholamine-stimulated cardiac contractility in early disease or even lead to arrhythmias originating from high cAMP levels at certain subcellular locations. These alterations of microdomain-associated signalling mechanisms might serve as a targets for more specific cardiovascular therapeutics.