Caveolin-3 Inhibits Cav3.2 (α1H) Currents and Regulates Hypertrophic Signaling in Ventricular Myocytes

Published on Feb 2, 2011in Biophysical Journal3.854
· DOI :10.1016/J.BPJ.2010.12.3085
Yogananda S. Markandeya8
Estimated H-index: 8
(UW: University of Wisconsin-Madison),
Jonathan M. Fahey1
Estimated H-index: 1
(UW: University of Wisconsin-Madison),
Ravi C. Balijepalli22
Estimated H-index: 22
(UW: University of Wisconsin-Madison)
Voltage gated T-type Ca2+ channel Cav3.2 subunit, responsible for T-type Ca2+ current (ICa,T) is expressed in different tissues including the heart and participates in Ca2+ influx, hormonal secretion, pacemaker activity and arrhythmia. The Cav3.2 channels are reported to be up regulated and contribute to the altered Ca2+ signaling and pathogenesis of cardiac hypertrophy via the activation of calcineurin/nuclear factor of activated T cells (NFAT) pathway. Caveolae containing scaffolding protein caveolin-3 (Cav-3) localize many ion channels and signaling proteins, and provide temporal and spatial regulation of intracellular Ca2+ in cardiomyocytes. However, the mechanism of altered Ca2+ signaling in cardiac hypertrophy is not clearly defined. We investigated the role of caveolae and Cav3.2 channels in the regulation of Ca2+ signaling during angiotensin-II induced cardiac hypertrophy in ventricular myocytes. Immunogold labeling and electron microscopy analysis demonstrated the co-localization of Cav3.2 channel and Cav-3 relative to caveolae in the ventricular myocytes. GST pull-down analysis confirmed that the N-terminus region of Cav-3 interacts with Cav3.2 channels. Impact of Cav-3 association with CaV3.2 was analyzed by whole cell patch clamp technique. Co-expression of Cav-3 specifically inhibited ICav3.2 in heterologously expressed HEK293 cells. In the neonatal ventricular myocytes, overexpression of Cav-3 inhibited ICa,T and specifically inhibited the adenovirus (AdCav3.2) mediated peak Cav3.2 currents. In addition, overexpression of Cav-3 prevented the angiotensin-II induced hypertrophic responses in neonatal mouse cardiomyocytes. Over expression of Cav-3 prevented the angiotensin-II induced translocation of NFAT4 to the nucleus and also inhibited the phosphorylation of extracellular signal-regulated kinase, ERK. Overall our results demonstrate that over expression of Cav-3 suppresses pathological hypertrophic responses in cardiomyocytes via the inhibition of the ICav3.2. We conclude that Cav-3 may play a crucial role in protective signaling mechanisms in the ventricular myocytes during hypertrophic cardiomyopathy.
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