High-Throughput Screens to Discover Small-Molecule Modulators of Ryanodine Receptor Calcium Release Channels.

ABSTRACT: Using time-resolved fluorescence resonance energy transfer (FRET), we have developed and validated the first high-throughput screening (HTS) method to discover compounds that modulate an intracellular Ca²⁺ channel, the ryanodine receptor (RyR), for therapeutic applications. Intracellular Ca²⁺ regulation is critical for striated muscle function, and RyR is a central player. At resting [Ca²⁺], an increased propensity of channel opening due to RyR dysregulation is associated with severe cardiac and skeletal myopathies, diabetes, and neurological disorders. This leaky state of the RyR is an attractive target for pharmacological agents to treat such pathologies. Our FRET-based HTS detects RyR binding of accessory proteins calmodulin (CaM) or FKBP12.6. Under cond

SUBMITTER: Rebbeck RT 

PROVIDER: S-EPMC5337111 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature