Role of cerebellar granule cell-specific GABA A receptor subtype in the differential sensitivity of [ 3H]ethynylbicycloorthobenzoate binding to GABA mimetics

Abstract

Binding of [ 3H]ethynylbicycloorthobenzoate ([ 3H]EBOB) to the γ-aminobutyric acid type A (GABA A) receptor of cultured cerebellar granule neurons is inhibited by GABA, muscimol and 3-aminopropanesulfonic acid with IC 50 values of 69–250 nM. Sensitivity to these GABA mimetics is lower by 3–4-fold for cerebellum and 10–20-fold for cerebral cortex, midbrain, and pons and medulla, a differential sensitivity by brain region and cell type consistent with earlier findings using tert-[ 35S]butylbicyclophosphorothionate and GABA. In contrast, the inhibitory potencies of two chloride channel blockers, α-endosulfan and picrotoxinin, do not differ in these assays. The hypothesis that this pharmacological profile is conferred by the α6 subunit specific to cerebellar granule cells is supported by the finding that forskolin (which downregulates the α6 subunit) but not the inactive dideoxyforskolin markedly decreases the sensitivity of [ 3H]EBOB binding to GABA without affecting inhibition by α-endosulfan.