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Jack A. Rall , Ph.D.
Professor
The Ohio State University Medical Center
Department
of Physiology and Cell Biology
1645 Neil Ave.
Columbus, OH 43210
Phone: (614) 292-6137
Fax: (614) 292-4888
Email:
rall.1@osu.edu
Education & Training:
Olivet College, Michigan, 1966, B.A. Mathematics
University of
Iowa, 1972, Ph.D. in Physiology & Biophysics
University
of California at Los Angeles (UCLA), 1972 – 1974, Postdoctoral
Fellow
Research Interest:
Our research goals are to understand the 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.
Selected Publications:
- Tikunova, S.B., J.A. Rall and J.P. Davis. (2002) Effect of
hydrophobic residue substitutions with glutamine on Ca2+ binding
and exchange with the N-domain of troponin C. Biochem.41:
6697-6705.
- Luo, Y., J.P. Davis, L.B. Smillie and J.A. Rall. (2002) Determinants
of relaxation rate in rabbit skinned skeletal muscle fibres. J.
Physiol. (London) 545: 887-901.
- Davis, J.P., J.A. Rall, P.J. Reiser, L.B. Smillie and S.B. Tikunova.
(2002) Engineering competitive Mg2+ binding into the first EF-hand
of skeletal troponin C. J. Biol. Chem.277:
49716-49726.
- Luo, Y., J.P. Davis, S.B. Tikunova, L.B. Smillie and J.A. Rall. Myofibrillar
determinants of rate of relaxation in skinned skeletal muscle fibers.
(2003) In MOLECULAR AND CELLULAR ASPECTS OF MUSCLE CONTRACTION.
H. Sugi, ed., Kluwer Academic/Plenum Publishers, pp. 573-582.
- Davis, J.P., J.A. Rall, C. Alionte and S.B. Tikunova. (2004) Mutations
of hydrophobic residues in the N-domain of troponin C affect calcium
binding and exchange with the troponin C-troponin I96-148 complex
and muscle force production. J. Biol. Chem. 279:
17348-17360.
- Davis, J.P., P.A. Wahr and J.A. Rall. Molecular aspects
of muscular contraction. (2004) In PRINCIPLES OF EXERCISE
BIOECHMISTRY. 3rd edition. J.R. Poortmans, ed.,
S. Karger, 46: 62-86.
- Rall, J.A. Energetics, mechanics and molecular engineering
of calcium cycling in skeletal muscle. (2005) In MYSTERIES
ABOUT THE SLIDING FILAMENT MECHANISM FIFTY YEARS AFTER ITS PROPOSAL. H.
Sugi, ed., Springer Science, pp. 183-192.
- Luo, Y. and J.A. Rall. Regulation of contraction kinetics
in skinned skeletal muscle fibers by calcium and troponin C. (2006) Archiv.
Biochem. Biophys. 456: 119-126.
- Norman, C., J.A. Rall, S.B. Tikunova and J.P. Davis. (2007) Modulation
of the rate of cardiac muscle contraction by troponin C constructs
with various calcium binding affinities. Am. J. Physiol.,
243:
H2580-H2587.
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