Identification of a dihydropyridine scaffold that blocks ryanodine receptors.

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 pot

SUBMITTER: Gunaratne GS 

PROVIDER: S-EPMC8760560 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature