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.

Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm

“…Ang II induces ERK activation resulting in an increase of MMP-2 expression in VSMCs [23]. MURC/Cavin-4 knockdown suppresses phenylephrine-induced ERK activation in cardiomyocytes [21]. MURC/Cavin-4-knockdown VSMCs also show suppressed ERK activation (Fig.…”

“…MURC/Cavin-4 knockout (MURC À/À ) mice have been previously described in detail [21]. ApoE À/À mice (C57BL/6) were obtained from Taconic Co., Ltd. (Germantown, NY, USA).…”

“…MURC À/À mice develop normally without any defects as described previously [21]. We subjected 12-week-old wild-type (WT) and MURC À/À mice to a model of AAA induced by periaortic application of 0.5 M CaCl 2 [24].…”

Caveolae and cancer: A new mechanical perspective

“…Indeed, Cavin4 mutations have recently been linked to human cardiopathies. [48,49] Recent structural studies based on electron microscopy and X-ray crystallography confirm that Cavins together with Cav1 are organizing a caveolar coat that plays an essential role in caveolae assembly. [16][17][18] Thus, it was shown that Cavin1 associated with Cavin2 or Cavin3 in a mutually exclusive manner at a ratio of 2 or 3 to 1 whereas Cavin1 associated with Cav1 at a 1-4 ratio.…”

MURC deficiency in smooth muscle attenuates pulmonary hypertension

“…Murc −/− and Murc floxed ( Murc fl/+ ) mice (C57BL/6J background) have been obtained using Cre-loxP and FLP-FRT system34. To generate Murc conditional knockout ( SM22Cre + Murc fl/fl ) mice, Murc fl/fl mice were bred with SM22Cre transgenic mice expressing Cre recombinase under the transcriptional control of the SMC-restricted SM22 promoter ( SM22Cre ) (C57BL/6J background, Jackson Laboratory).…”