Naohiro Yamaguchi, Ph.D.
Room 304, Bioengineering Building
Office: (843) 876-2487
Lab: Room 330 Bioengineering Building (843) 876-2497
Education:B.E. Biophysical Engineering, Osaka University, Japan 1993
M.E. Biophysical Engineering, Osaka University, Japan 1996
Ph.D. Biophysical Engineering, Osaka University, Japan 1999
Postdoctoral Fellow at University of North Carolina at Chapel Hill 2002
Calcium ions play critical roles in intracellular signaling of a variety of cells. In cardiac and skeletal muscle, transiently elevated Ca2+ concentrations during muscle action potentials initiate muscle contraction. In my laboratory we are studying how these Ca2+ transients are well regulated and how aberrant intracellular calcium homeostasis causes diseases in the cardiac and skeletal muscle.
(1) Heart failure is one of the leading causes of death in humans. In cardiac pathological studies, dysfunction of calcium transporting proteins is found to be implicated in cardiac hypertrophy and arrhythmia often resulting in heart failure. During an cardiac action potential Ca2+ influx through voltage-dependent L-type Ca2+ channels (Cav1.2) activates Ca2+ release channels (ryanodine receptors type2: RyR2s), which release Ca2+ from the sarcoplasmic reticulum (SR) by Ca2+-induced Ca2+ release (CICR).
I am currently interested in regulation mechanism of RyR2 and Cav1.2 by calmodulin, a ubiquitous cytoplasmic Ca2+ binding protein. During cardiac muscle contraction, elevated cytoplasmic Ca2+ and Ca2+-bound calmodulin regulate a number of proteins including these ion channels by a feedback mechanism. To address functional significance of calmodulin regulation of RyR2 and Cav1.2, I am characterizing wild type and mutant channels in vitro (heterologous cell expression) and in vivo (mutant mouse model). I have recently generated a genetically modified mouse impaired in calmodulin regulation of RyR2. Prolonged SR Ca2+ release was measured in cardiomyocytes isolated from mutant mouse hearts. In addition, cardiac hypertrophy and early death of the mutant mice were observed. This mutant mouse is a powerful model to analyze how abnormal Ca2+ homeostasis activates signaling pathways underlying cardiac hypertrophy.
(2) Intracellular Ca2+ transients in skeletal muscle are mediated by type1 ryanodine receptors calcium release channels (RyR1s). Missense mutations in RyR1 are associated with human skeletal myopathies including central core disease (CCD). A well-known molecular mechanism is that RyR1 mutations increase affinities for channel agonist, therefore causing intracellular Ca2+ overload. We hypothesize that an alternative mechanism underlying the skeletal myopathies is impairment of inhibitory regulation of RyR1. We recently have identified RyR domains involved in this Ca2+-dependent inactivation. We are characterizing biochemical and biophysical properties of the RyR1 harboring disease-associated point mutations in the identified domains. These studies are expected to provide a novel insight in dysfunctional Ca2+ homeostasis in skeletal pathology.
- Xu, L., Gomez, A. C., Pasek, D. A., Meissner, G., and Yamaguchi, N. (2017) Two EF-hand motifs in ryanodine receptor calcium release channels contribute to isoform-specific regulation by calmodulin. Cell Calcium 66, 62-70. PMID: 28807150. DOI: 10.1016/j.ceca.2017.05.013
- Gomez, A. C., Holford, T. W., and Yamaguchi, N. (2016) Malignant hyperthermia-associated mutations in S2-S3 cytoplasmic loop of ryanodine receptor calcium channel impair calcium-dependent inactivation. Am. J. Physiol.-Cell Physiol. 311, C749-C757. PMID: 27558158. DOI: 10.1152/ajpcell.00134.2016
- Gomez, A. C. and Yamaguchi, N. (2014) Two regions of the ryanodine receptor calcium channel are involved in Ca2+-dependent inactivation. Biochemistry 53, 1373-1379. PMID: 24521037. DOI: 10.1021/bi401586h
- Chakraborty, A., Pasek, D. A., Huang, T., Gomez, A. C., Yamaguchi, N., Anderson, M. E., and Meissner, G. (2014) Inhibition of CaMKII does not attenuate cardiac hypertrophy in mice with dysfunctional ryanodine receptor. PLoS One 9, e104338. PMID: 25093823. DOI: 10.1371/journal.pone.0104338
- Arnáiz-Cot, J. J., Damon, B. J., Zhang, X. H., Cleemann, L., Yamaguchi, N., Meissner, G., and Morad, M. (2013) Cardiac calcium signaling pathologies associated with defective calmodulin regulation of type 2 ryanodine receptor. J. Physiol. 591, 4287-4299. PMID: 23836685. DOI: 10.1113/jphysiol.2013.256123
- Yamaguchi, N., Chakraborty, A., Huang, T., Xu, L., Gomez, A. C., Pasek, D. A., and Meissner, G. (2013) Cardiac hypertrophy associated with impaired regulation of cardiac ryanodine receptor by calmodulin and S100A1. Am. J. Physiol.- Heart Circ. Physiol. 305, H86-H94. PMID: 23666671. DOI: 10.1152/ajpheart.00144.2013
- Rosa, A. O., Yamaguchi, N. and Morad, M. (2013) Mechanical regulation of native and the recombinant calcium channel. Cell Calcium 53, 264-74PMID: 23357406. DOI: 10.1016/j.ceca.2012.12.007
- Yamaguchi, N., Chakraborty, A., Pasek, D. A., Molkentin, J. D., and Meissner G. (2011) Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules. Am. J. Physiol.-Heart Circ. Physiol. 300, H2187-H2195. PMID: 21421818. DOI: 10.1152/ajpheart.00719.2010
- Yamaguchi, N., Prosser, B. L., Ghassemi, F., Xu, L., Pasek, D. A., Eu, J. P., Hernández-Ochoa, E. O., Cannon, B., Wilder, P. T., Lovering, R. M., Weber, D., Melzer, W., Schneider, M. F., and Meissner, G. (2011) Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1. Am. J. Physiol.-Cell Physiol. 300, C998-C1012. PMID: 21289290. DOI: 10.1152/ajpcell.00370.2010
- Sun, J., Yamaguchi, N., Xu, L., Eu, J. P., Stamler, J. S., and Meissner, G. (2008) Regulation of cardiac muscle ryanodine receptor by O2 tension and S-nitrosogultathione. Biochemistry 47, 13985-13990. PMID: 19053230. DOI: 1021/bi8012627
- Xu, L., Wang, Y., Yamaguchi N., Pasek, D. A., and Meissner, G. (2008) Single channel properties of heterotetrameric mutant RyR1 ion channels linked to core myopathies. J. Biol. Chem.283, 6321-6329. PMID: 18171678. DOI: 10.1074/jbc.M707353200
- Yamaguchi, N., Takahashi, N., Xu, L., Smithies, O., and Meissner, G. (2007) Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle calcium release channel. J. Clin. Invest. 117, 1344-1353. PMID: 17431507. DOI: 10.1172/JCI29515
- Yamaguchi, N. and Meissner, G. (2007) Does Ca2+/calmodulin-dependent protein kinase δc activate or inhibit the cardiac ryanodine receptor ion channel? Circ. Res. 100, 293-295. PMID: 17307966. DOI: 10.1161/01.RES.0000259327.56377.55
- Zhou, H.*, Yamaguchi, N.*, Xu, L., Wang, Y., Sewry, C., Jungbluth, H., Zorzato, F., Bertini, E., Muntoni, F., Meissner, G., and Treves, S. (2006) Characterization of recessive RYR1 mutations in core myopathies. Hum. Mol. Genet. 15, 2791-2803 (* Equal contribution). PMID: 16940308. DOI: 10.1093/hmg/ddl221
- Yamaguchi, N., Xu, L., Pasek, D. A., Evans, K. E., Chen, S. R. W., and Meissner, G. (2005) Calmodulin regulation and identification of calmodulin binding region of type-3 ryanodine receptor calcium channel. Biochemistry 44, 15074-15081. PMID: 16274254. DOI: 10.1021/bi051251t
- Yamaguchi, N., Xu, L., Evans, K. E., Pasek, D. A., and Meissner, G. (2004) Different regions in skeletal and cardiac muscle ryanodine receptors are involved in transducing the functional effects of calmodulin. J. Biol. Chem. 279, 36433-36439. PMID: 15215235. DOI: 10.1074/jbc.M405834200
- Yamaguchi, N., Xu, L., Pasek, D. A., Evans, K. E., and Meissner, G. (2003) Molecular basis of calmodulin binding to cardiac muscle Ca2+ release channel (ryanodine receptor). J. Biol. Chem. 278, 23480-23486. PMID: 12707260. DOI: 10.1074/jbc.M301125200
- Zorzato, F., Yamaguchi, N., Xu, L., Meissner, G., Müller, C. R., Pouliquin, P., Muntoni, F., Sewry, C., Girard T., and Treves, S. (2003) Clinical and functional effects of a deletion in a COOH-terminal loop of the skeletal muscle ryanodine receptor. Hum. Mol. Genet. 12, 379-388. PMID: 12566385. DOI: 10.1093/hmg/ddg032
- Yamaguchi, N., Xin, C., and Meissner, G. (2001) Identification of apocalmodulin and Ca2+-calmodulin regulatory domain in skeletal muscle Ca2+ release channel, ryanodine receptor. J. Biol. Chem. 276, 22579-22585. PMID: 11306590. DOI: 10.1074/jbc.M102729200