The tremorigen aflatrem is a positive allosteric modulator of the gamma-aminobutyric acidA receptor channel expressed in Xenopus oocytes.
Aflatrem, a mycotoxin from Aspergillus flavus, potentiates the gamma-aminobutyric acid (GABA)-induced chloride current. This positive allosteric regulatory action of aflatrem was quantitatively studied on the GABAA receptor channel expressed in Xenopus oocytes after injection with chick brain mRNA under voltage-clamp conditions. In this model system, aflatrem potentiates the current induced by 5 microM GABA in a concentration-dependent manner. Half-maximal potentiation was obtained with 2.4 microM aflatrem and maximal stimulation of the GABA (5 microM) response was more than 10-fold. The potentiation was not associated with a change of the reversal potential of the GABA-induced current. In the presence of 2 microM aflatrem, the GABA dose-response curve shifted to lower concentrations, with the Ka decreasing from 28 to 7 microM and the Hill coefficient, n, from 1.5 to 0.8, as measured at a membrane potential of -100 mV. At saturating concentration of GABA (250 microM), aflatrem (10 microM) was still able to enhance the current by about 21%. Further experiments suggest that the site of action of aflatrem on the GABAA receptor channel complex is different from that of benzodiazepines, pentobarbital, and picrotoxin. Aflatrem (10 microM) had no significant effect on the coexpressed voltage-dependent sodium and calcium channels and on the kainate channel. The potentiating action of aflatrem on the GABAA receptor channel may explain the initial symptoms of intoxication caused by aflatrem in vivo, i.e., diminished activity or immobility of the affected animal.
Yao
Y
Y
Department of Pharmacology, University of Bern, Switzerland.
Peter
A B
AB
Baur
R
R
Sigel
E
E
D000494:Allosteric Regulation; D000818:Animals; D018118:Chloride Channels; D002712:Chlorides / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008565:Membrane Proteins / Q000502:physiology*; D009183:Mycotoxins / Q000494:pharmacology*; D009865:Oocytes / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018118:Chloride Channels; D002712:Chlorides; D005442:Flumazenil; D007211:Indoles; D008565:Membrane Proteins; D009183:Mycotoxins; D010424:Pentobarbital; D010852:Picrotoxin; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C019239:aflatrem