Ryanodine Receptor Laboratory

Ryanodine Receptor Laboratory


Research Interests

Research in our laboratory focuses on a class of intracellular ion channels know as ryanodine receptors (RyRs). In mammals, there are three RyR isoforms. RyR1 and RyR2 are the predominate isoforms in skeletal and cardiac muscle, respectively where they are the primary efflux pathway for the release of calcium from the sarcoplasmic reticulum to activate contraction. RyR3 has a wide tissue distribution and contributes to calcium regulation in a variety of cell types. RyRs are the largest known ion channel and are regulated by a multitude of endogenous effectors, including ions, metabolites and regulatory proteins. Therefore, an area of interest is the regulation of these RyR channels by endogenous effectors; especially as it relates to altered contractile function associated with cardiac and skeletal disease, skeletal muscle fatigue and aging. We analyze channel function on multiples levels of organization. Sarcoplasmic reticulum vesicle [3H]ryanodine binding is used to examine large populations of channels. Individual channels are incorporated into artificial lipid bilayers in order to record single channel currents and assess channel kinetics. Calcium release from permeabilized muscle fibers provides a method of examining RyR function in situ. My research has two long-range goals. The first is to understand how intracellular calcium is regulated and how alterations in the regulation effects cell function. The second goal is to understand the RyR regulatory sites that could potentially be exploited for the development of pharmacological compounds to treat disorders of cellular calcium regulation.

Current Research Projects
  • Molecular Features Required for Ligand Action via the Ryanodine Receptor Adenine Nucleotide Binding Site  In this project we use radioligand binding and single channel recording combined with 3D-QSAR to define the requirements for ligand activation via the adenine nucleotide binding site.
  • RyR Function in Aging Muscle We are determining the effects of aging on RyR1 function using [3H]ryanodine binding and single channel recording. In addition we will define age-induced structural modifications of RyR1 using proteomic techniques
  • Structural Determinates of Calmodulin Regulation of RyRsThis collaborative project, with Dr. Jenny Yang (Ga. St.), uses biophysical and biochemical methods to determine the structural requirements for calmodulin regulation of RyR channels.

Research Opportunities

Research opportunities related to most of the projects listed above are available for graduate and undergraduate students. Dr. Balog is an adjunct member of the School of Biology. Undergraduate students are encouraged to take advantage of funding via the President’s Undergraduate Research Awards (Undergraduate Research Opportunities Program).

Recent Publications
  • Kampfer, A.J. and Balog, E.M. S-Adenosyl-L-methionine regulation of the cardiac ryanodine receptor involves multiple mechanisms. Biochem. 49:7600-7614, 2010.
  • Jiang J, Zhou Y, Zou J, Chen Y, Patel P, Yang JJ, and Balog EM. Site-Specific Modification of Calmodulin Ca2+ Affinity Tunes the Skeletal Muscle Ryanodine Receptor Activation Profile. Biochem J, 432:89-99, 2010.
  • Balog EM, Lockamy EL, Thomas DD, Ferrington DA. Site-Specific Methionine Oxidation Initiates Calmodulin Degradation by the 20S Proteasome. Biochemistry. 48:3005-3016, 2009.
  • Balog, E.M., L.E. Norton, N.R. Nitu, D.D. Thomas, and B.R. Fruen. Role of calmodulin methionine residues in mediating the productive association with cardiac ryanodine receptors. Am. J. Physiol. 290: H794-H799, 2006.
  • Balog, E.M., L.E. Norton, R.A. Bloomquist, R.L. Cornea, D.J. Black, C.F. Louis C.F., D.D. Thomas, and B.R. Fruen. Calmodulin oxidation and methionine to glutamine substitutions reveal methionine residues critical for functional interaction with RyR1. J. Biol. Chem. 278:15615-15621, 2003.
  • Fruen, B.R., D.J. Black, R.A. Bloomquist, J.M. Bardy, J.D. Johnson, C.F. Louis, and E.M. Balog. Regulation of the RyR1 and RyR2 Ca2+ release channel isoforms by Ca2+-insensitive mutants of calmodulin. Biochem. 42: 2740-2747, 2003.
  • Balog, E.M., N.H. Shomer, B.R. Fruen, and C.F. Louis. Divergent effects of the MHS Arg615→Cys mutation on the Ca2+ and Mg2+ dependence of RyR1. Biophys J. 81:2050-2058, 2001.
  • Balog, E.M. and R.H. Fitts. Effects of low intracellular pH and elevated extracellular Ca2+ on the charge movement currents of frog skeletal muscle. J. Appl. Physiol. 90: 228-234, 2001.
  • Balog, E.M., P.K. Kane, B.R. Fruen, and C.F. Louis. Mechanisms of inorganic phosphate regulation of the skeletal muscle SR Ca2+ release channel. Am. J. Physiol. 278:C601-C611, 2000.