Noriaki Ikemoto, Ph.D.
Senior Scientist
Malignant hyperthermia (skeletal muscle), central core disease (skeletal muscle), arrhythmogenic right ventricular dysplasia (heart muscle), polymorphic ventricular tachycardia (heart muscle)
Email: ikemoto at bbri.org

Research Summary
The process that is generally called excitation-contraction (e-c) coupling in muscle involves several important steps. Excitation initiated at the muscle cell surface (plasma membrane) is propagated into the cell through the transverse tubular (T-tubule) system. It spreads further to another membrane system, the sarcoplasmic reticulum (SR), and directly (in skeletal muscle), or indirectly (in cardiac muscle), stimulates a Ca2+ channel protein called the ryanodine receptor (RyR). This opens the Ca2+ channel located in the trans-membrane region of the SR, and the Ca2+ that has been accumulated in the SR is released into the sarcoplasm, causing muscle contraction. Our recent studies have led us to a ‘domain-switch’ model that involves inter-domain interactions serving as a key mechanism for Ca2+ channel regulation. In the resting muscle, the interacting key domains of the domain switch make close contact; this “zipped” configuration stabilizes the closed state of Ca2+ channel. Upon stimulation, the inter-domain contacts are weakened leading to an “unzipped” configuration, and this leads to Ca2+ channel opening and Ca2+ release. Abnormally regulated Ca2+ signaling leads to skeletal muscle disease, such as malignant hyperthermia (MH), and cardiac muscle disease, such as arrhythmogenic ventricular cardiomyopathy and stress-induced polymorphic ventricular tachycardia: two potentially fatal family-linked inheritable cardiomyopathies. Importantly, many mutations causing these diseases occur within the domain switch of RyR, indicating that the domain switch is an important site not only to understand the basic mechanism of channel activation, but also to understand the mechanism of pathogenesis. Since mutations in the domain switch produce severe aberrations of channel function in both skeletal and cardiac muscles, the domain switch must be a good target for the development of therapeutic agents. We recently found that dantrolene, a drug commonly used to treat MH, in fact binds to the domain switch, and stabilizes the zipped configuration, preventing unwanted domain unzipping caused by disease conditions. We also found that a new chemical compound JTV519, the 1,4-benzothiazepine derivatives, also prevents abnormal unzipping of the domain switch of cardiac RyR and the subsequent Ca2+ leak.

Selected Publications
Yamamoto, T., Yano, M., Xu, X., Uchinoumi, H., Tateishi, H., Mochizuki, M., Oda, T., Kobayashi, S., Ikemoto, N. & Matsuzaki, M. (2008). Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. Circulation 117, 762-72.

Gangopadhyay, J. P. & 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, 415-23.

Laver, D. R., Honen, B. N., Lamb, G. D. & Ikemoto, N. (2008). A domain peptide of the cardiac ryanodine receptor regulates channel sensitivity to luminal Ca(2+) via cytoplasmic Ca (2+) sites. Eur Biophys J 37, 455-67.

Laver, D. R., Hamada, T., Fessenden, J. D. & Ikemoto, N. (2007). The ryanodine receptor pore blocker neomycin also inhibits channel activity via a previously undescribed high-affinity Ca(2+) binding site. J Membr Biol 220, 11-20.

Bannister, M. L., Hamada, T., Murayama, T., Harvey, P. J., Casarotto, M. G., Dulhunty, A. F. & Ikemoto, N. (2007). Malignant hyperthermia mutation sites in the Leu2442-Pro2477 (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area. Biochem J 401, 333-9.

Hamada, T., Bannister, M. L. & Ikemoto, N. (2007). Peptide probe study of the role of interaction between the cytoplasmic and transmembrane domains of the ryanodine receptor in the channel regulation mechanism. Biochemistry 46, 4272-9.

Mochizuki, M., Yano, M., Oda, T., Tateishi, H., Kobayashi, S., Yamamoto, T., Ikeda, Y., Ohkusa, T., Ikemoto, N. & Matsuzaki, M. (2007). Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure. J Am Coll Cardiol 49, 1722-32.

Bannister, M. L. & Ikemoto, N. (2006). Effects of peptide C corresponding to the Glu724-Pro760 region of the II-III loop of the DHP (dihydropyridine) receptor alpha1 subunit on the domain- switch-mediated activation of RyR1 (ryanodine receptor 1) Ca2+ channels. Biochem J 394, 145-52.

Yang, Z., Ikemoto, N., Lamb, G. D. & Steele, D. S. (2006). The RyR2 central domain peptide DPc10 lowers the threshold for spontaneous Ca(2+) release in permeabilized cardiomyocytes. Cardiovasc Res 70, 475-85.
(Editorial for this paper: Fermandez-Velasco, M., Gomez, A. M., and Richard, S. (2006) Unzipping RyR2 in adult cardiomycytes: Getting closer to mechanisms of inherited ventricular arrhythmias? Cardiovasc. Res. 70, 107-409.)

Yano, M., Okuda, S., Oda, T., Tokuhisa, T., Tateishi, H., Mochizuki, M., Noma, T., Doi, M., Kobayashi, S., Yamamoto, T., Ikeda, Y., Ohkusa, T., Ikemoto, N. & Matsuzaki, M. (2005). Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure. Circulation 112, 3633-43.

Yano, M., Yamamoto, T., Ikemoto, N. & Matsuzaki, M. (2005). Abnormal ryanodine receptor function in heart failure. Pharmacol Ther 107, 377-91.

Kobayashi, S., Bannister, M. L., Gangopadhyay, J. P., Hamada, T., Parness, J. and Ikemoto, N. (2005) Dantrolene stabilizes domain interactions within the ryanodine receptor. J. Biol. Chem. 280, 6580–6587.

Kobayashi, S., Yamamoto, T., Parness, J., and Ikemoto, N. (2004) Antibody probe study of Ca2+ channel regulation by interdomain interaction within the ryanodine receptor.  Biochem. J. 323(3), 760-768.

Yamamoto, T., and Ikemoto, N. (2002) T-tubule depolarization-induced local events in the ryanodine receptor, as monitored with the fluorescent conformational probe incorporated by mediation of peptide A. J. Biol. Chem. 277, 984-992.

Yamamoto, T., and Ikemoto, N. (2002) Spectroscopic monitoring of local conformational changes during the intramolecular domain-domain interaction of the ryanodine receptor.  Biochemistry 41, 1492-1501.

Ikemoto, N., and Yamamoto, T. (2002) Regulation of calcium release by interdomain interaction within ryanodine receptors. Front Biosci. 7, d671-683 (invited review).

PubMed:
Click here for a list of publications (searches the National Library of Medicine's PubMed database.)