Identification of a dihydropyridine scaffold that blocks ryanodine receptors
Gihan S. Gunaratne,
Robyn T. Rebbeck,
Lindsey M. McGurran,
Yasheng Yan,
Thiago Arzua,
Talia Frolkis,
Daniel J. Sprague,
Xiaowen Bai,
Razvan L. Cornea,
Timothy F. Walseth,
Jonathan S. Marchant
Affiliations
Gihan S. Gunaratne
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA
Robyn T. Rebbeck
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Lindsey M. McGurran
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Yasheng Yan
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA
Thiago Arzua
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA
Talia Frolkis
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA
Daniel J. Sprague
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA
Xiaowen Bai
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA
Razvan L. Cornea
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Timothy F. Walseth
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Jonathan S. Marchant
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA; Corresponding author
Summary: 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.
