Gerhard Meissner, PhD

MeissnerGerhard.jpg Professor of Biochemistry & Biophysics

PHD - Technical University, Berlin

HONORS & AWARDS

  • NIH MERIT Award, 2010
  • Fellow of Biophysical Society, 1999

RESEARCH

Structure and Function of Intracellular Calcium Channels

The laboratory’s research focuses on defining the molecular basis of Ca2+ release channel (RyR) function in cardiac and skeletal muscle. RyRs are 2,200 kDa ion channels that release Ca2+ ions in response to an action potential from the sarcoplasmic reticulum (SR), an intracellular Ca2+-storing compartment in cardiac and skeletal muscle. A goal of the laboratory’s current work is to delineating the functional role of calmodulin in SR Ca2+ release. We showed that the cardiac and skeletal RyRs are regulated by calmodulin, a ubiquitous Ca2+ binding protein that controls a wide range of cellular functions. Our mutagenesis studies leading to the identification of the calmodulin regulatory sites of the RyR ion channels has enabled us to prepare and study genetically modified mice deficient in regulation of the cardiac and skeletal RyRs by calmodulin.Pink2 A second major goal is to understand the ion permeability properties of the skeletal muscle Ca2+ release channel (RyR1). RyR1 has a high conductance for monovalent (~800 pS with 250 mM K+ as conducting ion) and divalent cations (~150 pS with 50 mM Ca2+).The principal hypothesis to be tested by us is that a combined experimental and computational approach will substantially increase our knowledge of the molecular determinants responsible for channel gating and the high ion transport rates through the open RyR1. As our studies progress we expect to gain new insights in the complex mechanisms of RyR1 channel gating, ion conductance and selectivity and how these processes are altered by mutations in RyR1 linked to muscle diseases such as central core disease and malignant hyperthermia.

REPRESENTATIVE PUBLICATIONS pubmed.png (click for Full Publication List)

  • Arnáiz-Cot JJ, Damon BJ, Zhang XH, Cleemann L,Yamaguchi Y, Meissner G,  Morad M. Cardiac calcium signaling pathologies associated with defective calmodulin regulation of type 2 ryanodine receptor. J Physiol, in press.
  • Manno C, Figueroa L, Royer L, Pouvreau S, Lee CS,Volpe P, Nori A, Zhou J, Meissner G, Susan L. Hamilton SL, Ríos E. Altered Ca2+ concentration, permeability and buffering in the myofiber Ca2+ store of a mouse model of malignant hyperthermia. J Physiol 591:4439-4457, 2013.
  • 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. Amer J Physiol 305:H86-H94, 2013.
  • Mei Y, Xu L, Kramer HF, Tomberlin GH, Townsend C, Meissner G. Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the benzothiazepine derivative S107. PLoS One 8:e54208, 2013
  • Ramachandran S, Chakraborty A, Xu L, Mei Y, Samso M, Dokholyan NV, Meissner G. Structural determinants of skeletal muscle ryanodine receptor gating. J Biol Chem 288:6154-6165, 2013.
  • Meissner G. Ryanodine receptor calcium ion channels. In: Lennarz WJ, Lane MD (eds.) The Encyclopedia of Biological Chemistry. vol. 4, pp.195-198. Waltham, MA: Academic Press, 2013.
  • Petrotchenko EV, Yamaguchi N, Pasek DA, Borchers CH, Meissner G. Mass spectrometric analysis and mutagenesis predict involvement of multiple cysteines in redox regulation of RyR1. Res Reports Biol  2:13-21, 2011
  • Yamaguchi N, Prosser BL, Ghassemi F, Xu L, Pasek DA, Eu JP, Hernández-Ochoa EO, Cannon BR, Wilder PT, Lovering RM, David 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 300: C998-C1012, 2011
  • 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 300: H2187-H2195, 2011.
  • Ghassemi F, Vukcevic M,  Xu L, Zhou H, Meissner G, Muntoni F, Jungbluth H, Zorzato F,Treves S. A recessive ryanodine receptor 1 mutation in a CCD patient increases channel activity. Cell Calcium 5:192-197, 2009
  • Ramachandran  S, Serohijos AWR, Xu  L, Meissner  G, Dokholyan  NV. A structural model of the pore-forming region of the skeletal muscle ryanodine receptor (RyR1). PLoS Comput Biol 5:1-10, 2009
  • 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, 283:6321-6329, 2008
  • 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. Epub 2007
  • Lyfenko AD, Ducreux S, Wang Y, Xu L, Zorzato F, Ferreiro A, Meissner G, Treves S,  Dirksen RT. Two central core disease (CCD) deletions in the C-terminal region of RyR1 alter muscle EC coupling by distinct mechanisms. Human Mutation 28:61-68, 2007
  • Pouvreau S, Royer L, Yi J, Brum G, Meissner G, Ríos E, Zhou J. Ca(2+) sparks operated by membrane depolarization require isoform 3 ryanodine receptor channels in skeletal muscle. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5235-40. Epub 2007 Mar 14. Erratum in: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13531.
  • 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
  • Petrotchenko EV, Pasek D, Elms P, Dokholyan NV, Meissner G, Borchers CH. Lyfenko AD, Ducreux S, Wang Y, Xu L, Zorzato F, Ferreiro A, Meissner G, Treves S, Dirksen RT. Two central core disease (CCD) deletions in the C-terminal region of RYR1 alter muscle excitation-contraction (EC) coupling by distinct mechanisms. Hum Mutat. 2007 Jan;28(1):61-8
  • 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. Epub 2006 Aug 29. Erratum in: Hum Mol Genet. 2007 May 15;16(10):1269
  • Combining fluorescence detection and mass spectrometric analysis for comprehensive and quantitative analysis of redox-sensitive cysteines in native membrane proteins. Anal Chem. 2006 Dec 1;78(23):7959-66
  • Lee EH, Song DW, Lee JM, Meissner G, Allen PD, Kim do H. Occurrence of atypical Ca2+ transients in triadin-binding deficient-RYR1 mutants. Biochem Biophys Res Commun. 2006 Dec 29;351(4):909-14. Epub 2006
  • Du W, McMahon TJ, Zhang ZS, Stiber JA, Meissner G, Eu JP. Excitation-contraction coupling in airway smooth muscle. J Biol Chem. 2006 Oct 6;281(40):30143-51. Epub 2006
  • Xu L, Wang Y, Gillespie  D, Meissner G. Two rings of negative charges in the cytosolic vestibule of type-1 ryanodine receptor modulate ion fluxes. Biophys J 90:443-453, 2006
  • Zorzato F, Yamaguchi N, Xu L, Meissner G, Müller CR, Wang Y, Xu L, Pasek DA, D Gillespie D, Meissner G.  Probing the role of negatively charged amino acid residues in ion permeation of skeletal muscle ryanodine receptor. Biophys J 89:256-265, 2005
  • Gillespie D, Xu L, Wang Y, Meissner G. (De)constructing the ryanodine receptor: Modeling ion permeation and selectivity of the calcium release channel. J Phys Chem B 109:15598-15610, 2005
  • Gao L, Balshaw D, Xu L, Tripathy A, Xin C, Meissner G: Evidence for a role of the lumenal M3-M4 loop in skeletal muscle Ca2+ release channel (ryanodine receptor) activity and conductance. Biophys J 79:828-840, 2000. 
  • Eu JP, Sun J, Xu L, Stamler JS, Meissner G: The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. Cell 102:499-509, 2000
  • Lai FA, Erickson HP, Rousseau E, Liu QY, Meissner G: Purification and reconstitution of the calcium release channel from skeletal muscle.  Nature. 331:315-319, 1988.
  • Smith JS, Coronado R, Meissner G: Sarcoplasmic reticulum contains adenine nucleotide activated calcium channels.  Nature 316:446-449, 1985.

CONTACT INFORMATION

3047 Genetic Medicine Bldg
Campus Box 7260
Chapel Hill, NC 27599

Office: 919-966-5021
Fax: 919-966-2852

meissner@med.unc.edu

Lab Rooms: 3049A,B Genetic Med
Lab Phone: 919-966-3664