Enhancement of γ-aminobutyric acid-activated chloride channel currents by lanthanides in rat dorsal root ganglion neurons

Abstract

Lanthanum was previously reported to potentiate the GABA-induced chloride currents reversibly by acting at a distinct site on the GABAA receptor-channel complex (Ma and Narahashi, 1993). We now report that all other lanthanides tested enhanced the GABA responses with greater efficiencies and produced inward currents by themselves. The rank order of efficacies of lanthanides to potentiate the GABA responses and to generate currents correlated inversely with the hydrated ionic radii of these ions. The GABA-induced currents were recorded from the rat dorsal root ganglion neurons in primary culture by the whole-cell patch-clamp technique. Lanthanides at 1 mm reversibly potentiated the GABA responses (times of control): lutetium (Lu3+) 12.4 ± 0.1 > erbium (Er3+) 11.4 ± 0.2 > terbium (Tb3+) 9.3 ± 0.5 > europium (Eu3+) 5.4 ± 0.4 > neodymium (Nd3+) 4.1 ± 0.2 > cerium (Ce3+) 3.3 ± 0.2 > lanthanum (La3+) 2.4 ± 0.2 (n = 10). The enhancing effect of Tb3+ was dose dependent, with an EC50 356 ± 12 μM (n = 10), and weakly voltage dependent, increasing with hyperpolarization. The amplitudes of currents induced by various lanthanides (1 mM) were (percentage of 10 μM GABA-induced current) Lu3+ 101 ± 8 > Er3+ 57 ± 8 > Tb3+ 33 ± 3 > Eu3+ 20 ± 2 > Nd3+ 14 ± 2 ≈ Ce3+ 13 ± 0.6 > La3+ 10 ± 0.2 (n = 4). Tb3+ reversibly induced currents in a dose-dependent manner with an EC50 of 863 ± 0 μM (n = 5). The Tb3+-induced currents, which were not voltage dependent, were reversed in polarity at the chloride equilibrium potential. Both pentobarbital (100 μM) and chlordiazepoxide (50 μM) potentiated both GABA- and Tb3+-induced currents equally. The GABA receptor-channel antagonists bicuculline (10 μM), picrotoxin (10 μM), penicillin (500 μM), and Zn2+ (20 and 100 μM) all suppressed the Tb3+-induced current. We suggest that there is a distinct binding site on the GABA receptor-channel complex for the lanthanides and, at high concentrations, lanthanides may act on the GABA site or some other site to open the GABA-gated chloride channels. Copyright © 1993 Society for Neuroscience.