Jaya Pal Gangopadhyay, Ph.D.
Research Scientist
Ryanodine receptor, calmodulin, cardiac hypertrophy
Email: jaya at bbri.org

Research Summary
Calmodulin (CaM) plays a critical role in regulation of the ryanodine receptor (RyR), the major Ca2+ channel protein required for excitation-contraction (E-C) coupling of both skeletal (RyR1) and cardiac (RyR2) muscle. According to our recent work on RyR1, CaM regulation of RyR channels involves an intrinsic regulator built within the receptor, comprising of CaM-binding domain (CaMBD) and the CaM-like domain (CaMLD, which has CaM like properties). A tight interaction between CaMBD and CaMLD activates the channel (via formation of an ‘activation link’), while weakening or disruption of the interaction inhibits the channel. Under normal physiological conditions, CaM constitutively binds to CaMBD, thereby disrupting its interaction with CaMLD, thus preventing the formation of the ‘activation link’ to stabilize the closed state of RyR2 channels.

Cardiac hypertrophy is associated with sustained diastolic Ca2+ leak through RyR2 as the channel gets de-stabilized in otherwise resting conditions. Therefore, one of the pathogenic mechanisms could be the dissociation of CaM from the RyR2. If CaM dissociates from the RyR2, the CaMBD-CaMLD link would form spontaneously, resulting in the diastolic Ca2+ leak.

In the present project we are using neonatal cardiomyocytes to study the status of the intrinsic regulator of RyR2 in cardiac hypertrophy as well as the process of dissociation of CaM from the receptor to initiate the hypertrophy signal. 

The new information of CaM dissociation from RyR2 during the development of hypertrophy derived from this project will permit a better understanding of the pathogenic mechanisms of cardiac hypertrophy caused by defective CaMBD-CaMLD interactions within RyR2 and will help to develop a new therapeutic strategy targeting the CaM-modulatory domains of RyR2.

Selected Publications
Gangopadhyay JP, Ikemoto N. (2008) Interaction of the Lys(3614)-Asn(3643) calmodulin-binding domain with the Cys(4114)-Asn(4142) region of the type 1 ryanodine receptor is involved in the mechanism of Ca2+/agonist-induced channel activation. Biochem J. 411(2):415-23.
PMID: 18171325

Gangopadhyay JP, Ikemoto N. (2006) Role of the Met3534-Ala4271 region of the ryanodine receptor in the regulation of Ca2+ release induced by calmodulin binding domain peptide. Biophys J. 90(6):2015-26.
PMID: 16387763

Kobayashi S, Bannister ML, Gangopadhyay JP, Hamada T, Parness J, Ikemoto N. (2005) Dantrolene stabilizes domain interactions within the ryanodine receptor. J Biol Chem. 280(8):6580-7.
PMID: 15611117

Gangopadhyay JP, Grabarek Z, Ikemoto N. (2004) Fluorescence probe study of Ca2+-dependent interactions of calmodulin with calmodulin-binding peptides of the ryanodine receptor. Biochem Biophys Res Commun. 323(3):760-8.
PMID: 15381065

PubMed:
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