Gerhard Meissner

Research: Structure and regulation of intracellular calcium channels

Gerhard Meissner

Professor
(PhD - Technical University, Berlin)

120 Mason Farm Road, CB# 7260
3047 Genetic Medicine Building
Chapel Hill, NC 27599-7260
919-966-5021


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)

  • Mei Y, Xu L, Mowrey DD, Mendez Giraldez R, Wang Y, Pasek DA, Dokholyan NV, Meissner G. Channel gating dependence on pore lining helix glycine residues in skeletal muscle ryanodine receptor. J Biol Chem 290, 17535-17545, 2015.
  • Lavorato M, Huang TQ, Iyer VR, Perni S, Meissner G, Franzini-Armstrong C. Dyad content is reduced in cardiac myocytes of mice with impaired calmodulin regulation of RyR2. J Muscle Res Cell Motil 36:205-214, 2015.

  • Huang TQ, Zou MX, Pasek DA, Meissner G. mTOR signaling in mice with dysfunctional cardiac ryanodine receptor ion channel. J Receptor Ligand Channel Res 8: 43-51, 2015.

  • Gillespie D, Xu L, Meissner G. Selecting ions by size in a calcium channel: The ryanodine receptor case study. Biophys J 107:2263-2273, 2014.

  • Shirvanyants D, Ramachandran S, Mei Y, Xu L, Meissner G, Dokholyan NV. Pore dynamics and conductance of RyR1 transmembrane domain. Biophys J 106:2375-2384, 2014.

  • Yang Y, Guo T, Oda T, Chakraborty A, Chen L, Uchinoumi H, Knowlton A, Fruen B, Cornea R, Meissner G, Bers D. Cardiac myocyte Z-line calmodulin is mainly RyR2-bound and reduction is arrhythmogenic and occurs in heart failure. Circ Res 114:295-306, 2014.

  • 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, 591:4287-4299, 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 skeletalmuscle 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.


Lab Contact:

Lab Rooms:  3049A-B Genetic Medicine

Lab Phone: 919-966-3664 

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