Sandor Gyorke, Ph.D.

Professor Associate Director, Davis Heart & Lung Research Institute Director, Multiphoton/Confocal Microscopy Core Facility 507 Davis Heart & Lung Research Institute (office) 525/530 Davis Heart & Lung Research Institute (labs) 473 W. 12th Avenue Columbus  OH  43210 614-292-3969 (office) 614-292-3925 (lab) Sandor.Gyorke@osumc.edu

Education:
Ph.D., Physiology, Sechenov Institute of Physiology and Biochemistry
Academy of Sciences of USSR, Leningrad, USSR
Postdoctoral Training: University of Texas Medical Branch at Galveston

Research Area:
A major focus of our research group is the study of processes that regulate the contraction of the heart under both normal conditions and during cardiac disease. On a beat-to-beat basis, contraction of cells composing the heart is initiated by an increase of the amount of calcium in the cytosol. Most of this calcium is derived from the intracellular calcium store called the sarcoplasmic reticulum through specialized molecular gateways called ryanodine receptor channels.  Our research is concerned with the mechanisms that govern the gating activity of the ryanodine receptor channels and control the release of calcium from the sarcoplasmic reticulum. In addition, current work is devoted to alterations of intracellular calcium handling in disease conditions. Disorders of cardiac rhythm (arrhythmia) and pump function (heart failure) associated with abnormal calcium signaling are the leading causes of death in the US and worldwide.  Our goal is to gain fundamental insights into the mechanisms of these diseases in order to develop novel treatments. 

Techniques Available:

We use a variety of techniques including cellular electrophysiology and life-cell imaging combined with methods of molecular genetics, biochemistry and biophysics to gain better understandings of the regulation of intracellular calcium release in cardiac myocytes. The specific approaches include: confocal life-cell imaging of calcium and other intracellular regulatory molecules, such as cAMP, reactive oxygen species, in various cellular compartments (e.g. cytosol, sarcoplamic reticulum lumen and mitochondria) using fluorescent probes; recordings of membrane potential and transmembrane currents in cardiac myocytes using the patch-clamp technique; assessing protein-protein interactions inside living cells by measuring fluorescence resonance energy transfer (FRET); recording from single ryanodine receptor channels reconstituted into planar lipid bilayers; and, gene silencing and adenoviral-mediated gene transfer to study the role and behavior of different calcium regulatory proteins in cardiac myocytes.

Current Research Projects:
·  Molecular mechanisms of control of calcium release from the sarcoplasmic reticulum in cardiac myocytes: Modulation of ryanodine receptor by luminal calcium and accessory proteins.
·   Molecular mechanisms of inherited cardiac rhythm disorders and exercise-induced sudden cardiac death linked to mutations in ryanodine receptor and the calcium binding protein calsequestrin.
·  Molecular basis and cellular mechanisms of malignant arrhythmia following myocardial infarction.
·  The role and underlying causes of abnormal sarcoplasmic reticulum calcium release in chronic heart failure.

Intracellular Ca2+ handling in cardiomyocytes. Calcium transients begin with the initial influx of Ca2+ via L-type Ca2+ channels followed by Ca2+ release from the SR via ryanodine receptors (RyR2s), which culminates in contraction. During relaxation, Ca2+ reuptake occurs via the PLN-regulated Ca2+ pump SERCA2a. The major Ca2+ storing protein in the SR is calsequestrin (CASQ2). High [Ca2+]SR converts monomeric CASQ2 (bound to the RyR2-triadin-junctin complex) to the polymeric CASQ2 form that buffers Ca2+ and remains close to the complex in the jSR. Calstabin2 and monomeric CASQ2 bind to the complex and stabilize RyR2 activity. (From Györke et al, J Clin Invest 2007; 117:1758-1762)

Images of intracellular calcium transients acquired in a control cardiac myocyte (on the left) and in a monocyte overexpressing the calsequestrin mutant (CASQ2D307H). The myocytes were action potential stimulated at 2 Hz (at the arrows) in the presence of 1 um/L of isoproterenol. The myocyte expressing CASQ2D307H responds to each stimulation by two calcium transients presenting a case of cellular tachyarrhythmia.

Research Collaborations:

The laboratory has active collaborations with research groups at the Ohio State University as well as with investigators at other institutions in the US and internationally. Collaborative projects at OSU include studies of underlying causes of inherited arrhythmia caused by mutations in calsequestrin using genetic mouse models (with Dr. Muthu Periasamy) and elucidation of the role of abnormal intracellular calcium handling in arrhythmia following myocardial infarction and in chronic heart failure (with Drs. Cynthia Carnes, George Billman and David Feldman). Additional collaborative efforts include identification and characterization of new genetic defects in calcium regulatory proteins that cause inherited cardiac arrhythmia (with Dr. Silvia Priori, University of Pavia and Dr. Pompeo Volpe, University of Padova, Italy) and mathematical modeling of calcium signaling in cardiac myocytes (with Dr. Gregory Smith, The College of William and Mary).

Training and Employment Opportunities:

There are opportunities for graduate students and postdoctoral fellows to lead their own projects using state-of-the-art imaging, electrophysiological and molecular biology techniques that we employ to examine the regulation of intracellular calcium signaling and cardiac muscle function in normal and diseased states. For more information contact Dr. Gyorke, sandor.gyorke@osumc.edu.

Members of the Research Group:

Serge Viatchenko-Karpinski, Ph.D., Research Assistant Professor

Dmitry Terentyev, Ph.D., Research Scientist

Andriy Belevych, Ph.D., Research Scientist

Rada Terentieva, Research Assistant

Inna Gyorke, MS,  Senior Research Associate

Naresh Bal, Ph.D., Postdoctoral Researcher (co-mentored with Dr. M. Periasamy)

Yoshinori Nishijima, Ph.D., Postdoctoral Researcher (co-mentored with Dr. C. Carnes)

Selected Publications:
·  Terentyev D, Viatchenko-Karpinski S, Györke I, Volpe P, Williams SC, Györke S. Calsequestrin determines the functional size and stability of cardiac intracellular calcium stores: Mechanism for hereditary arrhythmia. Proc Natl Acad Sci USA, 2003; 100:11759-64.
·  Györke I, Hester N, Jones LR, Györke S. The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine receptor responsiveness to luminal calcium. Biophys J 2004; 86:2121-2128.
·  Viatchenko-Karpinski S, Terentyev D, Györke I, Terentyeva R, Volpe P, Priori SG, Napolitano C, Nori A, Williams SC, Györke S. Abnormal calcium signaling and sudden cardiac death associated with mutation of calsequestrin. Circ Res 2004; 94:471-477.
·  Kubalova Z, Terentyev D, Viatchenko-Karpinski S, Nishijima Y, Györke I, Terentyeva R, da Cuñha DN, Sridhar A, Feldman DS, Hamlin RL, Carnes CA, Györke S. Abnormal intrastore calcium signaling in chronic heart failure. Proc Natl Acad Sci U S A 2005; 02:14104-9.
·  Terentyev D, Nori A, Santoro M, Viatchenko-Karpinski S, Kubalova Z, Gyorke I, Terentyeva R, Vedamoorthyrao S, Blom NA, Valle G, Napolitano C, Williams SC, Volpe P, Priori SG, Gyorke S. Abnormal interactions of calsequestrin with the ryanodine receptor calcium release channel complex linked to exercise-induced sudden cardiac death. Circ Res 2006; 98:1151-8.
·  Terentyev D, Viatchenko-Karpinski S, Vedamoorthyrao S, Oduru S, Györke I, Williams SC, Györke S. Protein protein interactions between triadin and calsequestrin are involved in modulation of sarcoplasmic reticulum calcium release in cardiac myocytes. J Physiol 2007; 583:71-80.

Research Funding:
·  "Controlled and Uncontrollable Calcium Release in Heart" (PI) NIH, R01, 08/1999- 04/2010
·  "Abnormal intracellular calcium release in heart failure" (PI) NIH, R01, 05/2007-04/2011
·  "Dietary omega-3 fatty acids and sudden cardiac death" (Co-PI; George Billman PI) NIH, R01, 08/2007-06/2011
·  "NOS1/NOS3 functional effects on cardiac myocyte function" (Co-PI; Mark Ziolo PI), R01, 07/2006-06/2011

Awards Sponsored:
·  AHA Scientist Development Grant; Andriy Belevych (PI) “Regulation of cardiac excitation-contraction coupling by phosphodiesterase type 3 in normal and failing heart” 07/2006-06/2010.
·  AHA Scientist Development Grant; Dmitry Terentyev (PI) “Abnormal Protein-Protein Interactions in Sudden Cardiac Death” 07/2006- 06/2010.
·  AHA Scientist Development Grant; Sergiy Viatchenko-Karpinski (PI) “Altered adrenergic modulation of sarcoplasmic reticulum calcium release in myopathy induced by chronic treatment with isoproterenol” 07/2004-06/2008.
·  AHA, Post-doctoral fellowship, Great Rivers Affiliate; Yoshinori Nishijima (PI) “Calcium Regulation during Heart failure” 07/2007-06/2009