Kurt Beam, professor of physiology and biophysics at the University of Colorado at Denver, was awarded an MDA research grant totaling $300,000 over a period of three years to study two proteins that, when they malfunction, cause central core disease (CCD).
Muscle contraction in response to a nerve signal involves the interaction of two proteins: the dihydropyridine receptor (DHPR), which “senses” the electrical signal, and the ryanodine receptor (RyR1), which controls the release of calcium ions. Mutations in either one lead to CCD, as well as other muscle disorders. Beam will introduce the genes for these proteins into mouse muscle and nonmuscle cells. For both cell types, he says, researchers will measure the tiny electrical currents (less than a billionth of an ampere) produced by the DHPR. Fluorescence microscopy and calcium indicator dyes will be used to monitor movements of calcium inside individual cells; and confocal microscopy used to determine whether DHPRs and RyR1s are close to one another in the cells. The structure of these proteins then will be analyzed at a higher resolution by means of electron microscopy.
“Using these techniques, we hope to identify exactly what parts of the two proteins touch one another,” and how these sites of interaction and the overall shapes of the two proteins are affected by disease-causing mutations, Beam says.
“Although we have known for upward of 20 years that the DHPR and RyR1 are crucial for muscle contraction, we still do not understand the mechanism of their interaction, or exactly how disease-causing mutations affect this interaction,” says Beam. His research will attempt to better understand those interactions in order to define possible therapeutic targets for CCD and related muscle diseases.
Funding for this MDA grant began August 1, 2013.