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Naohiro Yamaguchi

Title
InstitutionMedical University of South Carolina
DepartmentRegenerative Medicine and Cell Biology
AddressP.O. Box MSC 508
BEB 304 office - BEB 330 lab
Bioengineering Bldg - 68 President St.
Phone843-876-2487
Fax843-792-0664
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    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.

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    Regenerative Medicine and Cell Biology

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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Chirasani VR, Xu L, Addis HG, Pasek DA, Dokholyan NV, Meissner G, Yamaguchi N. A central core disease mutation in the Ca2+ binding site of skeletal muscle ryanodine receptor impairs single channel regulation. Am J Physiol Cell Physiol. 2019 Jun 05. PMID: 31166712.
      View in: PubMed
    2. Xu L, Chirasani VR, Carter JS, Pasek DA, Dokholyan NV, Yamaguchi N, Meissner G. Ca2+-mediated activation of the skeletal-muscle ryanodine receptor ion channel. J Biol Chem. 2018 12 14; 293(50):19501-19509. PMID: 30341173.
      View in: PubMed
    3. Wei H, Zhang XH, Clift C, Yamaguchi N, Morad M. CRISPR/Cas9 Gene editing of RyR2 in human stem cell-derived cardiomyocytes provides a novel approach in investigating dysfunctional Ca2+ signaling. Cell Calcium. 2018 07; 73:104-111. PMID: 29730419.
      View in: PubMed
    4. Xu L, Gomez AC, Pasek DA, Meissner G, Yamaguchi N. Two EF-hand motifs in ryanodine receptor calcium release channels contribute to isoform-specific regulation by calmodulin. Cell Calcium. 2017 09; 66:62-70. PMID: 28807150.
      View in: PubMed
    5. Gomez AC, Holford TW, Yamaguchi N. Malignant hyperthermia-associated mutations in the S2-S3 cytoplasmic loop of type 1 ryanodine receptor calcium channel impair calcium-dependent inactivation. Am J Physiol Cell Physiol. 2016 Nov 01; 311(5):C749-C757. PMID: 27558158.
      View in: PubMed
    6. Chakraborty A, Pasek DA, Huang TQ, Gomez AC, Yamaguchi N, Anderson ME, Meissner G. Inhibition of CaMKII does not attenuate cardiac hypertrophy in mice with dysfunctional ryanodine receptor. PLoS One. 2014; 9(8):e104338. PMID: 25093823.
      View in: PubMed
    7. Gomez AC, Yamaguchi N. Two regions of the ryanodine receptor calcium channel are involved in Ca(2+)-dependent inactivation. Biochemistry. 2014 Mar 04; 53(8):1373-9. PMID: 24521037.
      View in: PubMed
    8. Arnáiz-Cot JJ, Damon BJ, Zhang XH, Cleemann L, Yamaguchi N, Meissner G, Morad M. Cardiac calcium signalling pathologies associated with defective calmodulin regulation of type 2 ryanodine receptor. J Physiol. 2013 Sep 01; 591(17):4287-99. PMID: 23836685.
      View in: PubMed
    9. Yamaguchi N, Chakraborty A, Huang TQ, Xu L, Gomez AC, Pasek DA, Meissner G. Cardiac hypertrophy associated with impaired regulation of cardiac ryanodine receptor by calmodulin and S100A1. Am J Physiol Heart Circ Physiol. 2013 Jul 01; 305(1):H86-94. PMID: 23666671.
      View in: PubMed
    10. Rosa AO, Yamaguchi N, Morad M. Mechanical regulation of native and the recombinant calcium channel. Cell Calcium. 2013 Apr; 53(4):264-74. PMID: 23357406.
      View in: PubMed
    11. Ishibashi D, Atarashi R, Fuse T, Nakagaki T, Yamaguchi N, Satoh K, Honda K, Nishida N. Protective role of interferon regulatory factor 3-mediated signaling against prion infection. J Virol. 2012 May; 86(9):4947-55. PMID: 22379081.
      View in: PubMed
    12. Yamaguchi N, Chakraborty A, Pasek DA, Molkentin JD, Meissner G. Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules. Am J Physiol Heart Circ Physiol. 2011 Jun; 300(6):H2187-95. PMID: 21421818.
      View in: PubMed
    13. Yamaguchi N, Prosser BL, Ghassemi F, Xu L, Pasek DA, Eu JP, Hernández-Ochoa EO, Cannon BR, Wilder PT, Lovering RM, Weber D, Melzer W, Schneider MF, Meissner G. Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1. Am J Physiol Cell Physiol. 2011 May; 300(5):C998-C1012. PMID: 21289290.
      View in: PubMed
    14. Petrotchenko EV, Yamaguchi N, Pasek DA, Borchers CH, Meissner G. Mass spectrometric analysis and mutagenesis predict involvement of multiple cysteines in redox regulation of the skeletal muscle ryanodine receptor ion channel complex. Res Rep Biol. 2011 Jan; 2011(2):13-21. PMID: 21603587.
      View in: PubMed
    15. Meissner G, Pasek DA, Yamaguchi N, Ramachandran S, Dokholyan NV, Tripathy A. Thermodynamics of calmodulin binding to cardiac and skeletal muscle ryanodine receptor ion channels. Proteins. 2009 Jan; 74(1):207-11. PMID: 18618700.
      View in: PubMed
    16. Sun J, Yamaguchi N, Xu L, Eu JP, Stamler JS, Meissner G. Regulation of the cardiac muscle ryanodine receptor by O(2) tension and S-nitrosoglutathione. Biochemistry. 2008 Dec 30; 47(52):13985-90. PMID: 19053230.
      View in: PubMed
    17. Stiber JA, Zhang ZS, Burch J, Eu JP, Zhang S, Truskey GA, Seth M, Yamaguchi N, Meissner G, Shah R, Worley PF, Williams RS, Rosenberg PB. Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity. Mol Cell Biol. 2008 Apr; 28(8):2637-47. PMID: 18268005.
      View in: PubMed
    18. Xu L, Wang Y, Yamaguchi N, Pasek DA, Meissner G. Single channel properties of heterotetrameric mutant RyR1 ion channels linked to core myopathies. J Biol Chem. 2008 Mar 07; 283(10):6321-9. PMID: 18171678.
      View in: PubMed
    19. Yamaguchi N, Takahashi N, Xu L, Smithies O, Meissner G. Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca release channel. J Clin Invest. 2007 May; 117(5):1344-53. PMID: 17431507.
      View in: PubMed
    20. Yamaguchi N, Meissner G. Does Ca2+/calmodulin-dependent protein kinase deltac activate or inhibit the cardiac ryanodine receptor ion channel? Circ Res. 2007 Feb 16; 100(3):293-5. PMID: 17307966.
      View in: PubMed
    21. Zhou H, Yamaguchi N, Xu L, Wang Y, Sewry C, Jungbluth H, Zorzato F, Bertini E, Muntoni F, Meissner G, Treves S. Characterization of recessive RYR1 mutations in core myopathies. Hum Mol Genet. 2006 Sep 15; 15(18):2791-803. PMID: 16940308.
      View in: PubMed
    22. Yamaguchi N, Xu L, Pasek DA, Evans KE, Chen SR, Meissner G. Calmodulin regulation and identification of calmodulin binding region of type-3 ryanodine receptor calcium release channel. Biochemistry. 2005 Nov 15; 44(45):15074-81. PMID: 16274254.
      View in: PubMed
    23. Yamaguchi N, Xu L, Evans KE, Pasek DA, Meissner G. Different regions in skeletal and cardiac muscle ryanodine receptors are involved in transducing the functional effects of calmodulin. J Biol Chem. 2004 Aug 27; 279(35):36433-9. PMID: 15215235.
      View in: PubMed
    24. Stange M, Xu L, Balshaw D, Yamaguchi N, Meissner G. Characterization of recombinant skeletal muscle (Ser-2843) and cardiac muscle (Ser-2809) ryanodine receptor phosphorylation mutants. J Biol Chem. 2003 Dec 19; 278(51):51693-702. PMID: 14532276.
      View in: PubMed
    25. Yamaguchi N, Xu L, Pasek DA, Evans KE, Meissner G. Molecular basis of calmodulin binding to cardiac muscle Ca(2+) release channel (ryanodine receptor). J Biol Chem. 2003 Jun 27; 278(26):23480-6. PMID: 12707260.
      View in: PubMed
    26. Zorzato F, Yamaguchi N, Xu L, Meissner G, Müller CR, Pouliquin P, Muntoni F, Sewry C, Girard T, Treves S. Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor. Hum Mol Genet. 2003 Feb 15; 12(4):379-88. PMID: 12566385.
      View in: PubMed
    27. O'Connell KM, Yamaguchi N, Meissner G, Dirksen RT. Calmodulin binding to the 3614-3643 region of RyR1 is not essential for excitation-contraction coupling in skeletal myotubes. J Gen Physiol. 2002 Sep; 120(3):337-47. PMID: 12198090.
      View in: PubMed
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