Activation of IP3 receptors by synthetic bisphosphate ligands

Abstract

Ca²⁺ release by D-myo-inositol 1,4,5-trisphosphate receptors (IP₃Rs) is widely considered to require the vicinal 4,5-bisphosphate motif of IP₃, with P-5 and P-4 engaging the α and β domains of the binding site; using synthesis and mutagenesis we show that the adenine of synthetic glyconucleotides, through an interaction with Arg504, can replace the interaction of either P-1 or P-5 with the α-domain producing, respectively, the most potent bisphosphate agonist yet synthesised and the first agonist of IP₃R without a vicinal bisphosphate motif; this will stimulate new approaches to IP₃R ligand design.