Abstract

Functional studies have indicated that, unlike most divalent cations, lanthanum increases both native and recombinant γ-aminobutyric acid (GABA) receptor (GABAR) currents. In the present study, we have examined whether lanthanum shows subunit-dependent selectivity for modification of currents from different GABAR isoforms. The effects of lanthanum on three different GABAR isoforms, α1β3γ2L, α6β3γ2L, and α6β3δ, were determined by transient expression of combinations of α1, α6, β3, γ2L, and δ subunit cDNAs in L929 fibroblasts. Whole-cell recording was used to determine the concentration-response curves for lanthanum for the three different isoforms at submaximal concentrations of GABA. Lanthanum displayed strong potentiation of α1β3γ2L GABAR currents consistent with earlier reports of potentiation of GABAR currents by lanthanum in neurons and recombinant GABAR isoforms. However, in contrast to the potentiation of α1β3γ2L GABAR currents by lanthanum, α6β3δ GABAR currents were strongly inhibited and α6β3γ2L GABAR currents were weakly inhibited by lanthanum. Interaction of lanthanum with GABAR isoforms was competitive, with lanthanum decreasing the EC₅₀ value for GABA of α1β3γ2L GABARs without changing the maximum current and increasing the EC₅₀ value for GABA of α6β3δ and α6β3γ2L GABAR currents (greater shift in EC₅₀ value in the α6β3δ compared with the α6β3γ2L GABARs) without changing the maximum GABAR current. Neither potentiation nor inhibition of GABAR currents by lanthanum showed any voltage dependence. These results suggest that 1) changing the α-subunit subtype from α1 to α6 altered the effect of lanthanum from potentiation to inhibition, 2) changing the γ2L subunit to the δ-subunit changed the level of maximal inhibition of α6 subtype-containing GABAR currents by lanthanum, and 3) the site for interaction with lanthanum probably was on the extracellular surface of GABARs.