Analysis of macroscopic ionic currents mediated by GABAĉ1 receptors during lanthanide modulation predicts novel states controlling channel gating

JUAN D. GOUTMAN; ARIEL L. ESCOBAR; DANIEL J. CALVO

BRITISH JOURNAL OF PHARMACOLOGY

Año: 2005 vol. 146 p. 1000 - 1009

0007-1188

1 Lanthanide-induced modulation of GABAC receptors expressed in Xenopus oocytes was studied. 2 We obtained two-electrode voltage-clamp recordings of ionic currents mediated by recombinant homomeric GABAr1 receptors and performed numerical simulations of kinetic models of the macroscopic ionic currents. 3 GABA-evoked chloride currents were potentiated by La3+, Lu3+ and Gd3+ 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 Lu3+ also induced receptor desensitization and decreased the deactivation rate of GABAr1 currents. 7 In the presence of 300 mM Lu3+, 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 GABAr1 receptors was modulated by Lu3+. 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 non-conducting desensitized state that closely reproduced the experimental results, two non-exclusive probable models of GABAr1 channels gating are p