Department of Regenerative Medicine and Cell biology

yamaguchi

Naohiro Yamaguchi, Ph.D.
Assistant Professor


Office: Bioengineering Building Room 304
Lab: Bioengineering Building Room 330
Phone: (843) 876-2487
Lab: (843) 876-2497

Email: yamaguch@musc.edu

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

Research Interests:

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. To progress in the treatment of heart diseases and the design of drugs, better understanding of the mechanisms underlying cardiac muscle Ca2+ signaling is required. Contraction and relaxation of cardiac muscle depend on the intracellular Ca2+. Cardiac muscle contraction is initiated by transient elevation of cytoplasmic Ca2+ concentration. 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). Multiple endogenous regulate Cav1.2 and RyR2 function, SR Ca2+ release, and thereby cardiac muscle contraction.

The goal of my research is to understand regulation mechanism of Ca2+ signaling in cardiac muscle cells. 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.

Recent Publications:

  1. Rosa, A. O., N. Yamaguchi and M. Morad. "Mechanical Regulation of Native and the Recombinant Calcium Channel." Cell Calcium 53, no. 4 (2013): 264-74 [PMID: 23357406]
  2. 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
  3. 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 (* Equal contribution)
  4. Meissner, G., Pasek, D. A., Yamaguchi, N., Ramachandran, S., Dokholyan, N. V., and Tripathy, A. (2009) Thermodynamics of calmodulin binding to cardiac and skeletal muscle ryanodine receptor ion channels. Proteins 74, 207-211
  5. 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
  6. 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
  7. 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
  8. 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 (Editorial)
  9. 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)
  10. 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
  11. 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
  12. Stange, M., Xu, L., Balshaw, D., Yamaguchi, N., and Meissner, G. (2003) Characterization of recombinant skeletal muscle (Ser2843) and cardiac muscle (Ser2809) ryanodine receptor phosphorylation mutants. J. Biol. Chem. 278, 51693-51702
  13. 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
  14. 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
  15. O’Connell, K. M. S., Yamaguchi, N., Meissner, G., and Dirksen, R. T. (2002) Calmodulin binding to the 3614-3643 region of RyR1 is not essential for excitation-contraction coupling in skeletal myotubes. J. Gen. Physiol. 120, 337-347
  16. 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
  17. Balshaw, D. M., Xu, L., Yamaguchi, N., Pasek, D. A., and Meissner, G. (2001) Calmodulin binding and inhibition of cardiac muscle calcium release channel (ryanodine receptor).J. Biol. Chem. 276, 20144-20153

 

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