Title: Identification of a novel inhibitor of type 1 ryanodine receptor (RyR1)
Speaker: Prof. Takashi Murayama, Juntendo University School of Medicine, Japan
Time: August 21st, Wednesday, 2:00 pm
Venue: Building 24#-C406
Host: Prof. Michael Yuchi
Abstract: Type 1 ryanodine receptor (RyR1) is a Ca2+ release channel in the sarcoplasmic reticulum and plays an important role in excitation-contraction coupling. Genetic mutations in RyR1 cause various skeletal muscle diseases including malignant hyperthermia (MH). Because themain underlying mechanism of the pathogenesis is hyperactive Ca2+ release by gain-of-function of the RyR1 channel, inhibition of RyR1 is expected to be a promising treatment for these diseases. Recently, we have developed a novel high-throughput screening (HTS) platform using time-lapse fluorescence measurement of Ca2+ in the endoplasmic reticulum (ER) to identify RyR1 inhibitors. By screening 1,535 compounds in a library of well-characterized drugs, we successfully identified four structurally-different compounds. Among them, oxolinic acid is highly RyR1 selective. Structure development of oxolinic acid successfully identified aderivative with 60-fold higher affinity than oxolinic acid. Therapeutic effects of oxolinic acid derivatives were tested using MH model mice. The highly quantitative nature and good correlation with the channel activity validate this HTS platform by ER Ca2+ measurement to explore novel drugs for RyR1-linked diseases.
Takashi Murayama is currently an associate professor in the Department of Pharmacology at Juntendo University School of Medicine, Japan. He got his MS degree in Department of Biology, Chiba University, Japan in 1990 and got Ph.D. degree in Department of Pharmacology, Juntendo University School of Medicine in 1996. He focuses on regulation of ryanodine receptor (RyR)/Ca2+ release channel and continues to investigate it for nearly 30 years. He haspublished more than 40 papers regarding this field. His group has recently developed efficient high-throughput screening platform for RyR inhibitors which have the potential for therapeutics against skeletal muscle and arrhythmogenic heart diseases.