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0026-895X/97/020328-08$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 51:328-335 (1997).

Contrasting Actions of Lanthanum on Different Recombinant gamma -Aminobutyric Acid Receptor Isoforms Expressed in L929 Fibroblasts

Nina C. Saxena,1 Torben R. Neelands, and Robert L. Macdonald

Departments of Neurology (N.C.S., T.R.N.) and Physiology (R.L.M.), University of Michigan Medical School, Ann Arbor, Michigan 48104-1687

Functional studies have indicated that, unlike most divalent cations, lanthanum increases both native and recombinant gamma -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, alpha 1beta 3gamma 2L, alpha 6beta 3gamma 2L, and alpha 6beta 3delta , were determined by transient expression of combinations of alpha 1, alpha 6, beta 3, gamma 2L, and delta  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 alpha 1beta 3gamma 2L 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 alpha 1beta 3gamma 2L GABAR currents by lanthanum, alpha 6beta 3delta GABAR currents were strongly inhibited and alpha 6beta 3gamma 2L GABAR currents were weakly inhibited by lanthanum. Interaction of lanthanum with GABAR isoforms was competitive, with lanthanum decreasing the EC50 value for GABA of alpha 1beta 3gamma 2L GABARs without changing the maximum current and increasing the EC50 value for GABA of alpha 6beta 3delta and alpha 6beta 3gamma 2L GABAR currents (greater shift in EC50 value in the alpha 6beta 3delta compared with the alpha 6beta 3gamma 2L 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 alpha -subunit subtype from alpha 1 to alpha 6 altered the effect of lanthanum from potentiation to inhibition, 2) changing the gamma 2L subunit to the delta -subunit changed the level of maximal inhibition of alpha 6 subtype-containing GABAR currents by lanthanum, and 3) the site for interaction with lanthanum probably was on the extracellular surface of GABARs.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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