title: Aberrant interaction of calmodulin with the ryanodine receptor develops hypertrophy in the neonatal cardiomyocyte.
abstract: 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 Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Boston Biomedical Research Institute, Watertown, MA 02472, USA. jaya@bbri.org
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Gangopadhyay
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ikemoto
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000276:immunology; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D000906:Antibodies; D002147:Calmodulin; D019332:Endothelin-1; D050778:NFATC Transcription Factors; D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2