Background: The adrenaline-beta-adrenoreceptor-cAMP-protein kinase A signaling pathway regulates heart rate and contractility. Although changes in contractility are associated with cardiovascular disease, surprisingly few drugs are available that modulate the cardiac myocyte cAMP system. Beta-blocking agents reduce cAMP levels only by 50%.
Objective: Compounds that interfere with the pathway at other levels are wanted as they may provide new tools for treatment of heart failure used alone or together with beta-blockers and may make therapy more potent and/or more targeted and avoid side effects.
Methods: Original findings and strategies for targeting protein-protein interactions are reviewed.
Results/conclusion: We have shown that A-kinase anchoring protein (AKAP)18delta is important for organizing the molecular machinery that mediates adrenergic control of calcium reabsorption into sarcoplasmic reticulum. Calcium reabsorption is essential for relaxation and filling of the heart and is the rate-limiting step for making the heart beat faster in response to adrenaline or noradrenaline. We conclude that targeting AKAP18delta may have application in manipulating calcium reabsorption and protecting the heart from adrenergic pacing at the level of specific signaling events in heart failure patients.