Suramin is a novel competitive antagonist selective to α1β2γ2 GABA_A over ρ1 GABA_C receptors

GABA_A and GABA_C receptors are both GABA-gated chloride channels with distinct pharmacological properties, mainly in their sensitivity to bicuculline and gabazine. In this study, we found that suramin, a purinergic receptor antagonist, is a novel competitive antagonist selective to GABA_A over GABA_C receptors. Specifically, suramin antagonized the GABA-induced current and the spontaneous opening current of the wild type α1β2γ2 GABA_A receptor with high-level expression in Xenopus oocytes. The antagonism was concentration dependent with an IC₅₀ that varied depending on the concentration of GABA, and with the lowest IC₅₀ of 0.43 μM when antagonizing the spontaneous current. Thus, its potency is slightly higher than bicuculline on the same GABA_A receptor. Suramin also antagonized the mouse native brain GABA receptors micro-transplanted into the Xenopus oocytes with its potency depending on the GABA concentration. In addition, in the presence of two fixed concentrations of suramin, the GABA concentration response of the receptor was shifted to the right without reduction of the maximum current. Thus, our results are consistent with that suramin is a competitive antagonist for the α1β2γ2 GABA_A receptor. Interestingly, the rank order of maximum allosteric inhibition (efficacy) of spontaneous current of the GABA_A receptor by three competitive antagonists was suramin > bicuculline > gabazine, similar to the rank order of their molecular weight. In contrast, similar to bicuculline, suramin has much lower potency in antagonizing the GABA-induced current of the ρ1 GABA_C receptor. In conclusion, we have identified a novel GABA_A receptor competitive antagonist, which is selective to the α1β2γ2 over ρ1 GABA receptors.