Analysis of macroscopic ionic currents mediated by GABA ρ1 receptors during lanthanide modulation predicts novel states controlling channel gating

Abstract

1 Lanthanide-induced modulation of GABA(C) receptors expressed in Xenopus oocytes was studied. 2 We obtained two-electrode voltage-clamp recordings of ionic currents mediated by recombinant homomeric GABA ρ1 receptors and performed numerical simulations of kinetic models of the macroscopic ionic currents. 3 GABA-evoked chloride currents were potentiated by La 3+, Lu 3+ and Gd 3+ in the micromolar range. 4 Lanthanide effects were rapid, reversible and voltage independent. 5 The degree of potentiation was reduced by increasing GABA concentration. 6 Lu 3+ also induced receptor desensitization and decreased the deactivation rate of GABA ρ1 currents. 7 In the presence of 300 μM Lu 3+, dose-response curves for GABA-evoked currents showed a significant enhancement of the maximum amplitude and an increase of the apparent affinity. 8 The rate of onset of TPMPA and picrotoxin antagonism of GABA ρ1 receptors was modulated by Lu 3+. 9 These results suggest that the potentiation of the anionic current was the result of a direct lanthanide-receptor interaction at a site capable of allosterically modulating channel properties. 10 Based on kinetic schemes, which included a second open state and a nonconducting desensitized state that closely reproduced the experimental results, two nonexclusive probable models of GABA ρ1 channels gating are proposed.