Abstract 11195: MURC/Cavin-4, a New Caveolar Scaffolding Protein for Activated ERK, Regulates Cardiac Hypertrophy Induced by α1-Adrenergic Agonist
[Background] Catecholamines and α1-adrenergic receptors (ARs), which are localized to caveolae in cardiomyocytes (CMs), cause cardiac hypertrophy. Recent studies have suggested that caveolae formation and function is regulated by the cavin-caveolin complex. Transgenic mice with cardiac-specific overexpression of muscle-restricted coiled-coil protein (MURC)/Cavin-4, a novel muscle-specific cavin isoform, exhibit cardiac hypertrophy. However, the role of MURC as a caveolae-related protein remains unknown. Here, we examined the role of MURC in signaling responsible for cardiac hypertrophy.
[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 caveolae enlargement, ERK activation, and subsequent 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 infusion of phenylephrine (PE), an α1-AR agonist. ERK activation and subsequent cardiac 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 activated ERK has been reported to accumulate at caveolae of CMs, we then examined the role of MURC in the accumulation of ERK at caveolae. Immunohistochemistry showed colocalization of MURC and phosphorylated ERK1/2 at the plasma membrane of CMs, and immunoprecipitation revealed their association, suggesting that MURC is necessary to accumulate activated ERK at caveolae in CMs.
[Conclusion] MURC/Cavin-4 is a novel caveolar scaffolding protein for activated ERK in CMs, and its scaffolding function is necessary to elicit efficient signaling of the α1-AR/ERK pathway at caveolae in α1-AR agonist-induced cardiac hypertrophy.
- © 2012 by American Heart Association, Inc.