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 Ca(2+) release (IICR), at sub-maximal concentrations of InsP(3), in a biphasic manner consistent with two inhibition constants (K(i)'s 6.7 and > or =400 microM). 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 Ca(2+) stores, which release Ca(2+) in either a fast or slow fashion. This study has shown that the rate constants for Ca(2+) release from both the fast and slow populations are reduced by paxilline (100 microM) by about 70% and 60%, respectively. Detailed analysis of the way different concentrations of paxilline inhibit the rate constants for Ca(2+) release indicates that the population of Ca(2+) stores that contribute to the slower phase of Ca(2+) release is more sensitive to the inhibitory action of paxilline.
Longland
C L
CL
School of Biosciences, University of Birmingham, Edgbaston, B152TT, Birmingham, UK.
Dyer
J L
JL
Michelangeli
F
F
D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009183:Mycotoxins / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism
D015220:Calcium Channels; D007211:Indoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009183:Mycotoxins; D018160:Receptors, Cytoplasmic and Nuclear; C048220:paxilline; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium