Abstract
In this study, we identified two previously described kinase inhibitors-- LY2784544 and GSK2636771-- as novel GPR39 agonists by unbiased small-molecule-based screening using a βarrestin recruitment screening approach (PRESTO-Tango). We characterized the signaling of LY2784544 and GSK2636771 and compared it with a previously described "GPR39-selective" agonist GPR39-C3 at both canonical and non-canonical signaling pathways. Unexpectedly, all three compounds displayed probe-dependent and pathway-dependent allosteric modulation by zinc. These findings reveal an unexpected role of zinc as an allosteric potentiator of small-molecule-induced activation of GPR39.
- Orphan GPCRs
- Gi family
- Gs family
- Gq/11 family
- Arrestins
- Calcium
- Func. analysis receptor/ion channel mutants
- The American Society for Pharmacology and Experimental Therapeutics