γ-aminobutyric acid type A receptors modulate neurosteroid binding to the voltage-dependent anion channel.

Neurosteroids modulate the function of γ-aminobutyric acid type A (GABAA) receptors in the brain. We showed that GABAA receptors modulate neurosteroid interactions with VDAC. GABA enhanced [3H]6-AziP labeling of VDAC in a concentration-dependent manner. This effect of GABA was prevented by the GABAA receptor antagonists gabazine and picrotoxin. Studies with brain tissue from mice deficient for VDAC showed that GABA enhanced [3H]6-AziP labeling of VDAC2 and VDAC1. GABA enhanced photolabeling of VDAC in HEK cells expressing γ2L-subunit, suggesting that the γ2L-subunit is required for the interaction of GABAA receptors with VDAC. VDAC1 and VDAC2 both co-immunoprecipitated with GABAA receptors in rat brain membranes. Collectively, the data provide evidence for a direct signaling pathway between the synaptic plasma membrane GABAA receptor and VDAC, a mitochondrial outer membrane protein.