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Br J Pharmacol
2005 Dec 01;1467:1000-9. doi: 10.1038/sj.bjp.0706411.
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Analysis of macroscopic ionic currents mediated by GABArho1 receptors during lanthanide modulation predicts novel states controlling channel gating.
Goutman JD, Escobar AL, Calvo DJ.
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Lanthanide-induced modulation of GABA(C) receptors expressed in Xenopus oocytes was studied. We obtained two-electrode voltage-clamp recordings of ionic currents mediated by recombinant homomeric GABArho(1) receptors and performed numerical simulations of kinetic models of the macroscopic ionic currents.GABA-evoked chloride currents were potentiated by La(3+), Lu(3+) and Gd(3+) in the micromolar range. Lanthanide effects were rapid, reversible and voltage independent. The degree of potentiation was reduced by increasing GABA concentration.Lu(3+) also induced receptor desensitization and decreased the deactivation rate of GABArho(1) currents. In the presence of 300 microM Lu(3+), dose-response curves for GABA-evoked currents showed a significant enhancement of the maximum amplitude and an increase of the apparent affinity. The rate of onset of TPMPA and picrotoxin antagonism of GABArho(1) receptors was modulated by Lu(3+). 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. 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 GABArho(1) channels gating are proposed.
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