Suramin is a novel competitive antagonist selective to alpha 1 beta 2 gamma 2 GABA(A) over rho 1 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 alpha 1 beta 2 gamma 2 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 mu M 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 alpha 1 beta 2 gamma 2 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 rho 1 GABA(C) receptor. In conclusion, we have identified a novel GABA(A) receptor competitive antagonist, which is selective to the alpha 1 beta 2 gamma 2 over rho 1 GABA receptors.