期刊
BIOCHEMICAL JOURNAL
卷 438, 期 -, 页码 379-387出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20110203
关键词
activation link; anti-CaMBD antibody; calmodulin (CaM); calmodulin-binding domain (CaMBD); calmodulin kinase II (CaMKII); nuclear factor of activated T-cells (NFAT); ryanodine receptor (RyR)
资金
- National Institute of Health [R01 HL072841]
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 CaM BD and CaMLD of RyR is a key step in the development of hypertrophy in cultured cardiomyocytes.
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