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Mechanism-based therapies for heart failure and cardiac arrhythmias
Published on October 1, 2007 47 min
A selection of talks on Biochemistry
The ERK1/2 MAPK cascade
- Prof. Melanie H. Cobb
- University of Texas Southwestern Medical Center at Dallas, USA
Amino acid conjugation: mechanism and enzymology
- Dr. Kathleen Knights
- Flinders University, Australia
Hello, I am Dr. Andrew Marks from Columbia University. I would like to present work from my laboratory on mechanism-based therapies for heart failure and cardiac arrhythmias. For the next 45 minutes or so, I will review for you work that I have done in the laboratory over the past 20 years that has focused on the ryanodine receptor or cardiac calcium release channel shown here, on the right of this slide, releasing small red balls that represent the calcium that drives muscle contraction.
This cartoon, adapted from a review by Dr. Donald Bers published in Nature in 2002, shows the basic mechanisms of excitation-contraction coupling that involve the ryanodine receptor. What is shown in this picture is a cartoon or representation of a heart muscle cell. The action potential electrically activates the heart muscle and causes a depolarization of the muscle membrane, which opens a calcium channel that is blocked by the clinically-used calcium channel blockers. Calcium entry from outside the cell then activates the much larger ryanodine receptor, or calcium release channel, which is located on the sarcoplasmic reticulum, and it is the release of calcium from the sarcoplasmic reticulum that raises the concentration of calcium in the muscle cell approximately 10 times, and this is the signal that activates the contraction of the myofilaments to cause the contraction of heart muscle. A similar mechanism works in skeletal muscle. So this is the mechanism whereby the electrical energy from the action potential is translated into a mechanical energy that causes muscle contraction. About 20 years ago, as I will describe to you, I discovered a small regulatory protein that we now call calstabin, or calcium release channel stabilizing binding protein, and it is also known as the FK binding protein or FKBP. And this calstabin, or FKBP, has several critically-important functions in regulating the calcium release channel that I will soon describe to you and has become an important therapeutic target for both heart failure and sudden cardiac death.