Compartmentation of β 2 -adrenoceptor stimulated cAMP responses by phosphodiesterase types 2 and 3 in cardiac ventricular myocytes

• Published in: British journal of pharmacology 2021-04, Vol.178 (7), p.1574-1587
• Main Authors: Rudokas, Michael W, Post, John P, Sataray-Rodriguez, Alejandra, Sherpa, Rinzhin T, Moshal, Karni S, Agarwal, Shailesh R, Harvey, Robert D
• Format: Article
• Language: English
• Subjects: Animals; Cyclic AMP; Heart Ventricles; Myocytes, Cardiac; Phosphoric Diester Hydrolases; Rats; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.15382

In cardiac myocytes, cyclic AMP (cAMP) produced by both β - and β -adrenoceptors increases L-type Ca channel activity and myocyte contraction. However, only cAMP produced by β -adrenoceptors enhances myocyte relaxation through phospholamban-dependent regulation of the sarco/endoplasmic reticulum Ca ATPase 2 (SERCA2). Here we have tested the hypothesis that stimulation of β -adrenoceptors produces a cAMP signal that is unable to reach SERCA2 and determine what role, if any, phosphodiesterase (PDE) activity plays in this compartmentation. The cAMP responses produced by β -and β -adrenoceptor stimulation were studied in adult rat ventricular myocytes using two different fluorescence resonance energy transfer (FRET)-based biosensors, the Epac2-camps, which is expressed uniformly throughout the cytoplasm of the entire cell and the Epac2-αKAP, which is targeted to the SERCA2 signalling complex. Selective activation of β - or β -adrenoceptors produced cAMP responses detected by Epac2-camps. However, only stimulation of β -adrenoceptors produced a cAMP response detected by Epac2-αKAP. Yet, stimulation of β -adrenoceptors was able to produce a cAMP signal detected by Epac2-αKAP in the presence of selective inhibitors of PDE2 or PDE3, but not PDE4. These results support the conclusion that cAMP produced by β -adrenoceptor stimulation was not able to reach subcellular locations where the SERCA2 pump is located. Furthermore, this compartmentalized response is due at least in part to PDE2 and PDE3 activity. This discovery could lead to novel PDE-based therapeutic treatments aimed at correcting cardiac relaxation defects associated with certain forms of heart failure.