We have shown previously that the inter-domain interaction between the two domains of RyR (ryanodine receptor), CaMBD [CaM (calmodulin)-binding domain] and CaMLD (CaM-like domain), activates the Ca2+ channel, and this process is called activation-link formation [Gangopadhyay and Ikemoto (2008) Biochem. J. 411, 415–423]. Thus CaM that is bound to CaMBD is expected to interfere the activation-link formation, thereby stabilizing the closed state of the channel under normal conditions. In the present paper, we report that, upon stimulation of neonatal cardiomyocytes with the pro-hypertrophy agonist ET-1 (endothelin-1), CaM dissociates from the RyR, which induces a series of intracellular events: increased frequency of Ca2+ transients, translocation of the signalling molecules CaM, CaMKII (CaM kinase II) and the transcription factor NFAT (nuclear factor of activated T-cells) to the nucleus. These events then lead to the development of hypertrophy. Importantly, an anti-CaMBD antibody that interferes with activation-link formation prevented all of these intracellular events triggered by ET-1 and prevented the development of hypertrophy. These results indicate that the aberrant formation of the activation link between CaMBD and CaMLD of RyR is a key step in the development of hypertrophy in cultured cardiomyocytes.
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Research Article|
August 12 2011
Aberrant interaction of calmodulin with the ryanodine receptor develops hypertrophy in the neonatal cardiomyocyte
Jaya P. Gangopadhyay;
Jaya P. Gangopadhyay
1
*Boston Biomedical Research Institute, Watertown, MA 02472, U.S.A.
1To whom correspondence should be addressed (email jaya@bbri.org).
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Noriaki Ikemoto
Noriaki Ikemoto
*Boston Biomedical Research Institute, Watertown, MA 02472, U.S.A.
†Department of Neurology, Harvard Medical School, Boston, MA 02115, U.S.A.
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Publisher: Portland Press Ltd
Received:
January 31 2011
Revision Received:
April 29 2011
Accepted:
June 08 2011
Accepted Manuscript online:
June 08 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (2): 379–387.
Article history
Received:
January 31 2011
Revision Received:
April 29 2011
Accepted:
June 08 2011
Accepted Manuscript online:
June 08 2011
Citation
Jaya P. Gangopadhyay, Noriaki Ikemoto; Aberrant interaction of calmodulin with the ryanodine receptor develops hypertrophy in the neonatal cardiomyocyte. Biochem J 1 September 2011; 438 (2): 379–387. doi: https://doi.org/10.1042/BJ20110203
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