The potential use of AKAP18delta as a drug target in heart failure patients.
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.


CONCLUSIONS
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.
Lygren
Birgitte
B
Postdoctoral fellow Biotechnology Centre of Oslo, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
Taskén
Kjetil
K
D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016503:Drug Delivery Systems; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D000099211:Phospholamban
D054758:A Kinase Anchor Proteins; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D000099211:Phospholamban; C112596:AKAP7 protein, human