The mycotoxin paxilline inhibits the cerebellar inositol 1,4,5-trisphosphate receptor

Paxilline, a tremorgenic alkaloid mycotoxin produced by Penicillium paxilline, is a reversible inhibitor of the cerebellar inositol 1,4,5-trisphophate (InsP(3)) receptor. It inhibits the amount or extent of InsP(3)-induced Ca2+ release (IICR), at sub-maximal concentrations of InsP(3), in a biphasic manner consistent with two inhibition constants (K-i's 6.7 and greater than or equal to 400 muM) As paxilline does not affect InsP(3) binding to the receptor, it can be considered a non-competitive inhibitor. The fact that IICR is biphasic has been interpreted as there being two populations of InsP(3)-sensitive Ca2+ stores, which release Ca2+ in either a fast or slow fashion. This study has shown that the rate constants for Ca2+ release from both the fast and slow populations are reduced by paxilline (100 muM) by about 70% and 60%, respectively. Detailed analysis of the way different concentrations of paxilline inhibit the rate constants for Ca2+ release indicates that the population of Ca2+ stores that contribute to the slower phase of Ca2+ release is more sensitive to the inhibitory action of paxilline. (C) 2000 Elsevier Science B.V. All rights reserved.