Adenophostins, newly discovered metabolites of Penicillium brevicompactum, act as potent agonists of the inositol 1,4,5-trisphosphate receptor.

Potent inositol 1,4,6-trisphosphate (IPS) receptor agonists, adenophostin A and B, were found from fungal products.In spite of the striking structural difference from IPS, adenophostins were found to inhibit [sHIIP~ binding more potently than IPS: the Ki values for adenophostin A and B were both calculated to be 0.18 PM, while that of IPS was 15 11~.Adenophostins induced Ca2+ release both from cerebellar microsomes and from intracellular Caz+ stores in permeabilized NG108-16 cells.Adenophostins at concentration as low as 1 PM produced a significant Ca2+ release from cerebellar microsomes, and their activities were 100-fold more potent than IPS.In addition, heparin, an IPS receptor antagonist, completely blocked the Ca2+ releasing activity of adenophostins.Adenophostins were resistant to phosphorylation and dephosphorylation by IPS-metabolizing enzymes, thereby providing a possible explanation for their prolonged activities.Adenophostin also bound to plasma membrane IPS receptor with a high affinity and inhibited [SH]IPs binding to jurkat human T-cell plasma membranes: the ICm value for adenophostin A was 0.98 PM.Adenophostin may prove to be a powerful tool for investigating the physiological properties of IPS and its receptor.Inositol 1,4,5-trisphosphate (IP3),l the product of receptormediated hydrolysis of phosphatidylinositol 4,5-bisphosphate, is a second messenger which releases Ca2+ fiom intracellular Ca2+ stores in a wide variety of cell types (1).Areceptor protein that contains both an IP3 recognition site and a Ca2+ channel was isolated from cerebellum (2-6).Recently, the presence of