Abstract 15384: MURC Promotes Recruitment of Erk1/2 to Caveolae of the Plasma Membrane and Concentric Cardiac Hypertrophy Induced by a1-adrenergic Stimulation
Background: The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes (CMs),α1-ARs locate in flask-shaped membrane microdomains known as caveolae. Caveolae require both caveolins and cavins for their biogenesis and function. However, molecular interactions of caveolar components in cardiomyocytes remain poorly understood. Here, we show that MURC, a caveolae-related protein, regulates α1-AR-induced cardiomyocyte hypertrophy through the enhancement of ERK1/2 activation in caveolae.
Methods and Results: Immunoprecipitation and bimolecular fluorescence complementation assays revealed that MURC bound to cavin-1 and -2 and caveolin-3 at the plasma membrane of CMs. Immunoelectron microscopy showed that MURC was localized to caveolae and T-tubules of CMs. Immunohistochemistry demonstrated that MURC was also colocalized with α1A- and α1B-ARs at the plasma membrane of CMs. Overexpression of MURC in CMs induced ERK activation and hypertrophy. To assess the requirement of MURC for cardiac hypertrophy in vivo, MURC-knockout (KO) and wild-type (WT) mice were subjected to a model of cardiac hypertrophy induced by phenylephrine (PE) infusion. ERK activation and concentric hypertrophy induced by PE were significantly suppressed in MURC-KO hearts compared with WT hearts, although caveolae were retained in CMs of MURC-KO mice, indicating that MURC is prerequisite for PE-induced ERK activation and cardiac hypertrophy, but not caveolae formation. Since ERK proteins has been reported to activate at the plasma membrane of CMs, we then examined an involvement of MURC in ERK activation at the plasma membrane. MURC was colocalized with phosphorylated and total ERK1/2 at the plasma membrane of CMs, and MURC knockdown reduced phosphorylated ERK accumulation at the plasma membrane, suggesting that MURC is necessary to recruit ERK proteins at caveolae in CMs.
Conclusion: MURC facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a novel insight into molecular mechanisms underlying caveolae-mediated signaling in hypertrophy.
- © 2013 by American Heart Association, Inc.