Depolarization of the transverse tubule (TT) membrane of a skeletal muscle fiber initiates a sequence of steps leading to contractile activation. Later steps involve Ca release from the sarcoplasmic reticulum (SR), elevation Delta Ca of myoplasmic free calcium concentration and CA binding to contractile filaments. The initial voltage-sensitive step in the depolarization-contraction coupling process may be movement of intramembrane charge (Q) within the TT membrane. In order to study the mechanisms involved in control of SR calcium release by Q and other factors, we have developed techniques for simultaneously monitoring both Delta Ca and Q in voltage-clamped cut segments of single skeletal muscle fibers containing the Ca indicator dye antipyrylazo III. Delta Ca records can be used to empirically characterize the systems responsible for removing Ca from the myoplasm. Using this information, the time course of SR calcium release can be calculated from Delta Ca. Calcium release and Q will be monitored for a variety of pulse protocols in order to test whether the two parameters exhibit the appropriate relationships for Q to control SR Ca permeability. Calcium depletion from the SR and a relatively fast inactivation of release that may be calcium dependent will both be characterized. This information will allow calculation of the activation of SR calcium release for comparison with Q. The molecular basis for signal transmission from TT to SR will be investigated. Knowledge about this important step in muscle activation may allow design of more effective or more specific skeletal muscle relaxant drugs and will allow tests for possible modification of this step in various pathological conditions. An inactivation of calcium release by elevated resting myoplasmic calcium levels that might be related to muscle """"""""weakness"""""""" under certain conditions will also be studied.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023346-04
Application #
3406700
Study Section
Physiology Study Section (PHY)
Project Start
1985-07-01
Project End
1991-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Zhang, Yingfan; Rodney, George G; Schneider, Martin F (2005) Effects of azumolene on Ca2+ sparks in skeletal muscle fibers. J Pharmacol Exp Ther 314:94-102
Rodney, George G; Wilson, Gerald M; Schneider, Martin F (2005) A calmodulin binding domain of RyR increases activation of spontaneous Ca2+ sparks in frog skeletal muscle. J Biol Chem 280:11713-22
Schneider, Martin F; Rodney, George G (2004) Peptide and protein modulation of local Ca2+ release events in permeabilized skeletal muscle fibers. Biol Res 37:613-6
Rodney, George G; Schneider, Martin F (2003) Calmodulin modulates initiation but not termination of spontaneous Ca2+ sparks in frog skeletal muscle. Biophys J 85:921-32
Chun, Lois G; Ward, Christopher W; Schneider, Martin F (2003) Ca2+ sparks are initiated by Ca2+ entry in embryonic mouse skeletal muscle and decrease in frequency postnatally. Am J Physiol Cell Physiol 285:C686-97
Shtifman, Alexander; Ward, Christopher W; Yamamoto, Takeshi et al. (2002) Interdomain interactions within ryanodine receptors regulate Ca2+ spark frequency in skeletal muscle. J Gen Physiol 119:15-32
Schneider, Martin F; Ward, Christopher W (2002) Initiation and termination of calcium sparks in skeletal muscle. Front Biosci 7:d1212-22
Lacampagne, A; Klein, M G; Ward, C W et al. (2000) Two mechanisms for termination of individual Ca2+ sparks in skeletal muscle. Proc Natl Acad Sci U S A 97:7823-8
Shtifman, A; Ward, C W; Wang, J et al. (2000) Effects of imperatoxin A on local sarcoplasmic reticulum Ca(2+) release in frog skeletal muscle. Biophys J 79:814-27
Klein, M G; Lacampagne, A; Schneider, M F (1999) A repetitive mode of activation of discrete Ca2+ release events (Ca2+ sparks) in frog skeletal muscle fibres. J Physiol 515 ( Pt 2):391-411

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