Modulation of Ionotropic GABA Receptors by 6-Methoxyflavanone and 6-Methoxyflavone

Abstract

We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type α1/α2β2γ2L GABAA and ρ1 GABAC receptors and on mutant ρ1I307S, ρ1W328M, ρ1I307S/W328M GABAC receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABAA receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABAA receptors. 6-Methoxyflavanone inhibited [(3)H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1β2 GABAA receptors and it's partial agonist action at ρ1W328M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.