Jack A. Rall, Ph.D.

Professor Vice Chair, Department of Physiology and Cell Biology 203 Hamilton Hall 1645 Neil Avenue Columbus  OH  43210-1218 rall.1@osu.edu

Education:
B.A., Mathematics and Physical Education, Olivet College, Olivet, MI
Ph.D., Physiology and Biophysics, University of Iowa, Iowa City, IA
Postdoctoral Fellow, Physiology, UCLA, Los Angeles, CA

Research Area:
Cellular and molecular control of striated muscle contraction and relaxation by calcium.

Research Interests:
Our research goals are to understand the basic mechanisms that control muscle relaxation and to engineer proteins that modulate these mechanisms. The speed of relaxation is determined by the rate of Ca²⁺ removal from the contractile elements and rate of cross-bridge detachment. Ca²⁺ removal is controlled by the rate of Ca²⁺:  a) dissociation from the regulatory protein troponin C (TnC), b) uptake by a membrane bound Ca²⁺ pump and c) binding to the soluble protein parvalbumin. The aim is to understand the quantitative contribution of these factors to the rate of relaxation in different muscle types.

Our hypothesis is that the Ca²⁺ dissociation rate from TnC is an important determinant of muscle relaxation rate. To test this hypothesis, we:  a) generated mutants of TnC that exhibit varying Ca²⁺ affinities and Ca²⁺ dissociation rates, b) developed a simplified in vitro system to screen mutant properties and c) tested the effects of TnC mutants on relaxation rate in skinned skeletal muscle fibers. We found that the Ca²⁺ dissociation rate from TnC complexed with troponin I (TnI), its binding partner in muscle, is similar to the Ca²⁺ dissociation rate from TnC in myofibril suspensions and is similar to muscle relaxation rate. Furthermore, the muscle relaxation rate can be slowed by a mutant of TnC that slows Ca²⁺ dissociation from the TnC-TnI complex but cannot be increased by a TnC mutant with faster Ca²⁺ dissociation rate. These results suggest that the Ca²⁺ dissociation rate from TnC and the rate of cross-bridge detachment are comparable and contribute equally to the rate of muscle relaxation.

We are now studying the molecular mechanisms of these effects and comparing the regulatory mechanisms in skeletal muscle with those in cardiac muscle. 

 We employ the tools of molecular biology, biochemistry and physiology. Techniques include protein mutagenesis, stopped flow technology to determine the kinetics of Ca²⁺ exchange with Ca²⁺-binding proteins in solution and in myofibrils, pulsed laser light activation of Ca²⁺- chelating compounds that lead to rapid changes in intracellular Ca²⁺ that either activate or inactivate muscle fibers and measurements of muscle mechanics.

Laboratory Members:

Recent Publications:
• Norman C, Rall JA, Tikunova SB, Davis JP. Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities. Am J Physiol 243:H2580-H2587, 2007.
• Luo Y, Rall JA. Regulation of contraction kinetics in skinned skeletal muscle fibers by calcium and troponin C. Archiv Biochem Biophys 456:119-126, 2006.
• Rall JA. Energetics, mechanics and molecular engineering of calcium cycling in skeletal muscle. In: MYSTERIES ABOUT THE SLIDING FILAMENT MECHANISM FIFTY YEARS AFTER ITS PROPOSAL. H Sugi, ed, Springer Science, pp 183-192, 2005.
• Davis JP, Rall JA, Alionte C, Tikunova SB. Mutations of hydrophobic residues in the N-domain of troponin C affect calcium binding and exchange with the troponin C-troponin I_96-148 complex and muscle force production. J Biol Chem 279:17348-17360, 2004.
• Davis JP, Wahr PA, Rall JA. Molecular aspects of muscular contraction. In: PRINCIPLES OF EXERCISE BIOECHMISTRY, 3^rd edition, JR Poortmans, ed, S Karger, 46:62-86, 2004.

Current Laboratory Funding:
• MODULATION OF RELAXATION RATE IN STRIATED MUSCLE.  NIH (R01 AR20792, years 22-26) 1/1/05-12/31/09, $1,480,050 (total cost), J.A. Rall (P.I.); S.B. Tikunova (Co-P.I.).
• INFLUENCE OF TROPONIN C ON THE RATE OF CARDIAC MUSCLE RELAXATION.  NIH (K99 Pathway to Independence Award), 12/1/06 – 11/30/08, $180,000 (total cost), S. B. Tikunova (P.I.); J. A. Rall (Sponsor), P. Janssen (Co-Sponsor)