4 June 2013

Getting to the Heart of Signaling

Analysis of phosphorylated proteins from the hearts of mice given drugs targeting beta-adrenergic receptors may aid in treating heart disease.

Stimulation of beta-adrenergic receptors (beta-ARs) is an essential component of the fight-or-flight response in human physiology, which initiates phosphorylation-dependent cell signaling cascades, resulting in increased cardiac output. Although beta-AR inhibitors (beta-blockers) are widely prescribed in the clinic the majority of their downstream cellular targets remain to be elucidated. Delineating the signaling pathways regulated through site-specific phosphorylation as a result of beta-AR stimulation bears important etiological and therapeutic implications in diseases such as hypertension and heart failure.

A KU/SUND research team led by Professor Olsen performed quantitative phosphoproteomics on murine hearts and identified 670 specific protein phosphorylation sites that are regulated in response to in-vivo beta-adrenergic stimulation when compared to treatment with beta-blockers. The researchers find that the proteins phosphorylated upon stimulation are primarily involved in striated muscle contraction, hypertrophic cardiomyopathy, and serine/threonine kinase activity. The study provides evidence for involvement of specific protein kinases not previously linked with the beta-adrenergic response and it also reveals regulated sites on ion channels and transporters essential for the rhythmic beating of the heart. For one novel phosphorylation site, the researchers demonstrate that phosphorylation increases current conduction of the cardiac voltage-gated potassium channel subunit Kv7.1 that plays an important role in cardiac repolarization. The study is published in Science Signaling: http://stke.sciencemag.org/.

Title: In Vivo Phosphoproteomics Analysis Reveals the Cardiac Targets of beta-Adrenergic Receptor Signaling

Authors: Alicia Lundby, Martin N. Andersen, Annette B. Steffensen, Heiko Horn, Christian D. Kelstrup, Chiara Francavilla, Lars J. Jensen, Nicole Schmitt, Morten B. Thomsen and Jesper V. Olsen

www.SCIENCESIGNALING.org 4 June 2013 Vol 6 Issue 278 rs11