MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors.

Abstract

The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as "caveolae." Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR-induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy.

• Authors: Takehiro Ogata, Daisuke Naito, Naohiko Nakanishi, Yukiko K Hayashi, Takuya Taniguchi, Kotaro Miyagawa, Tetsuro Hamaoka, Naoki Maruyama, Satoaki Matoba, Koji Ikeda, Hiroyuki Yamada, Hidemasa Oh, Tomomi Ueyama
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 10 Pg. 3811-6 (Mar 11 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24567387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cavin4 protein, mouse
• DNA Primers
• Muscle Proteins
• Receptors, Adrenergic, alpha-1

Topics

• Animals
• Blotting, Western
• Cardiomegaly (metabolism)
• Caveolae (metabolism)
• DNA Primers (genetics)
• Echocardiography
• Immunoprecipitation
• MAP Kinase Signaling System (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Electron, Transmission
• Microscopy, Fluorescence
• Muscle Proteins (genetics, metabolism)
• Myocytes, Cardiac (metabolism)
• RNA Interference
• Rats
• Rats, Wistar
• Real-Time Polymerase Chain Reaction
• Receptors, Adrenergic, alpha-1 (metabolism)