Grant: Operating Grant

In the heart, muscle contraction is triggered by the release of calcium from the internal calcium stores called the sarcoplasmic reticulum. To ensure stable muscle contraction and relaxation, calcium release, once initiated, is rapidly terminated to allow the released calcium to be pumped back to the internal stores and to set off for the next cycle of calcium release and reuptake. The mechanism underlying the initiation of calcium release has been extensively studied and is well defined, but how calcium release is terminated remains the least understood question in the field of muscle contraction. Recent studies have suggested that the calcium level inside the internal stores controls the opening and closing of the calcium release channel located in the internal calcium stores. It is this calcium release channel that determines the initiation and termination of calcium release. It is becoming increasingly clear that alterations in the initiation or termination of calcium release are major causes of many cardiac diseases. The objective of this research proposal is to investigate how calcium release is terminated and how defective termination of calcium release leads to cardiac abnormalities. Recent studies from Dr. Chen's laboratory have provided some important clues to these fundamental questions. It appears that the calcium release channel has its own calcium sensor that tells the channel to open or close depending on the level of calcium inside the stores. A variety of cutting-edge technologies will be employed to study the role of this putative calcium sensor in calcium release termination and how this process is affected by disease-causing mutations in the calcium release channel. These proposed studies would shed novel and exciting insights into the molecular basis and regulation of Ca2+ release termination, and have profound implications for the prevention and treatment of various heart diseases.