Microdomain Switch of cGMP-Regulated Phosphodiesterases Leads to ANP-Induced Augmentation of β-Adrenoceptor-Stimulated Contractility in Early Cardiac Hypertrophy

Rationale:Cyclic nucleotides are second messengers that regulate cardiomyocyte function through compartmentalized signaling in discrete subcellular microdomains. However, the role of different microdomains and their changes in cardiac disease are not well understood. Objective:To directly visualize alterations in β-adrenergic receptor–associated cAMP and cGMP microdomain signaling in early cardiac disease. Methods and Results:Unexpectedly, measurements of cell shortening revealed augmented β-adrenergic receptor–stimulated cardiomyocyte contractility by atrial natriuretic peptide/cGMP signaling in early cardiac hypertrophy after transverse aortic constriction, which was in sharp contrast to well-documented β-adrenergic and natriuretic peptide signaling desensitization during chronic disease. Real-time cAMP analysis in β1- and β2-adrenergic receptor–associated membrane microdomains using a novel membrane-targeted Forster resonance energy transfer–based biosensor transgenically expressed in mice revealed tha...