Adenophostins, newly discovered metabolites of Penicillium brevicompactum, act as potent agonists of the inositol 1,4,5-trisphosphate receptor.
Potent inositol 1,4,5-trisphosphate (IP3) receptor agonists, adenophostin A and B, were found from fungal products. In spite of the striking structural difference from IP3, adenophostins were found to inhibit [3H]IP3 binding more potently than IP3: the Ki values for adenophostin A and B were both calculated to be 0.18 nM, while that of IP3 was 15 nM. Adenophostins induced Ca2+ release both from cerebellar microsomes and from intracellular Ca2+ stores in permeabilized NG108-15 cells. Adenophostins at concentration as low as 1 nM produced a significant Ca2+ release from cerebellar microsomes, and their activities were 100-fold more potent than IP3. In addition, heparin, an IP3 receptor antagonist, completely blocked the Ca2+ releasing activity of adenophostins. Adenophostins were resistant to phosphorylation and dephosphorylation by IP3-metabolizing enzymes, thereby providing a possible explanation for their prolonged activities. Adenophostin also bound to plasma membrane IP3 receptor with a high affinity and inhibited [3H]IP3 binding to jurkat human T-cell plasma membranes: the IC50 value for adenophostin A was 0.95 nM. Adenophostin may prove to be a powerful tool for investigating the physiological properties of IP3 and its receptor.
Takahashi
M
M
Fermentation Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Tanzawa
K
K
Takahashi
S
S
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D000072181:Inositol Polyphosphate 5-Phosphatases; D010407:Penicillium / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C085029:adenophostin A; C085030:adenophostin B; D015544:Inositol 1,4,5-Trisphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D000241:Adenosine; D002118:Calcium