Does oxytocin interact with GABAA receptors?
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Ethanol at low millimolar levels enhances the engagement of gamma-aminobutyric acid
type A receptors incorporating the δ subunit (δ-GABAAR). In the present study, utilizing
[3H]muscimol and [3H]EBOB binding assays, we examined the impact of oxytocin on GABA
agonist binding to cerebellar and forebrain membranes from male and female rats, as well as
recombinant GABAA α6β3γ2 and α6β3δ receptors. In cerebellar membranes, oxytocin exhibited
no significant alteration in [3H]muscimol binding, indicating an absence of influence on GABA
agonist binding to cerebellar tissues in rats of both genders. Conversely, in forebrain membranes,
oxytocin displayed a slight contrasting effects on basal [3H]EBOB binding in male and female
rats. In the male forebrain, oxytocin enhances [3H]EBOB binding, suggesting counteracting
effect against GABA. In contrast, in the female forebrain, oxytocin reduces [3H]EBOB binding,
implying a potentiating effect on GABA activity on GABA-induced [3H]EBOB displacement.
Furthermore, utilizing recombinant α6β3γ2 and α6β3δ receptors, oxytocin demonstrated
differential effects on [3H]EBOB binding. An increased binding percentage to α6β3γ2 receptors
oxytocin did not influence the binding activity of [3H]EBOB binding in that receptor compared
to control, while decreasing [3H]EBOB binding to α6β3δ receptors, suggesting increased
inhibitory activity. Additionally, molecular docking was employed to explore potential binding
interactions between oxytocin and the GABAA α6β3δ receptor, focusing on the subunit
interfaces involving the δ subunit. Conventional docking to a rigid receptor model resulted in
less optimal binding interactions than induced fit docking (IFD) that allows for flexible protein
side chains during the docking process. The findings underscore the importance of polar
interactions and optimal hydrophobic residue placement for oxytocin’s binding affinity.