Faculty Collaboration Database

Identification of a dihydropyridine scaffold that blocks ryanodine receptors. iScience 2022 Jan 21;25(1):103706

Date

01/22/2022

Pubmed ID

35059610

Pubmed Central ID

PMC8760560

DOI

10.1016/j.isci.2021.103706

Scopus ID

2-s2.0-85122630600 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca²⁺ release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart, and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer's disease. Therefore, there is considerable interest in therapeutically targeting RyRs to normalize Ca²⁺ homeostasis in scenarios involving RyR dysfunction. Here, a simple invertebrate screening platform was used to discover new chemotypes targeting RyRs. The approach measured Ca²⁺ signals evoked by cyclic adenosine 5'-diphosphate ribose, a second messenger that sensitizes RyRs. From a 1,534-compound screen, FLI-06 (currently described as a Notch "inhibitor") was identified as a potent blocker of RyR activity. Two closely related tyrosine kinase inhibitors that stimulate and inhibit Ca²⁺ release through RyRs were also resolved. Therefore, this simple screen yielded RyR scaffolds tractable for development and revealed an unexpected linkage between RyRs and trafficking events in the early secretory pathway.

Author List

Gunaratne GS, Rebbeck RT, McGurran LM, Yan Y, Arzua T, Frolkis T, Sprague DJ, Bai X, Cornea RL, Walseth TF, Marchant JS

Authors

Xiaowen Bai PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Daniel J. Sprague PhD Postdoctoral Fellow in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin