FUNCTIONAL-PROPERTIES OF RECOMBINANT GABA(A) RECEPTORS COMPOSED OF SINGLE OR MULTIPLE BETA-SUBUNIT SUBTYPES

GABA(A) receptor (GABAR) isoforms in the central nervous system are co mposed of combinations of alpha(1 - 6), beta(1 - 4), gamma(1 - 4), del ta(1) and epsilon(1) subunit subtypes arranged in a pentamer. Many reg ions of the brain express high levels of mRNA encoding several differe nt subunits and even multiple subunit subtypes. The stoichiometry of G ABAR isoforms is unclear, and the number and identity of individual su bunit subtypes that are coassembled remain uncertain. To examine the r ole of beta subunit subtypes in the functional properties of GABARS an d to determine whether multiple beta subtypes can be coassembled in fu nctional GABARs, plasmids containing cDNAs encoding rat beta 1 and/or beta 3, alpha 5 and gamma 2L subtypes were cotransfected into L929 fib roblasts. The properties of the expressed receptor populations were de termined using whole-cell and single-channel recording techniques. The alpha 5 beta 1 gamma 2L isoform was less sensitive to GABA than the a lpha 5 beta 3 gamma 2L isoform. alpha 5 beta 1 gamma 2L isoform curren ts were also insensitive to the allosteric modulator loreclezole, whil e alpha 5 beta 3 gamma 2L isoform currents were strongly potentiated b y loreclezole. Fibroblasts transfected with plasmids containing cDNAs for both beta 1 and beta 3 subtypes along with alpha 5 and gamma 2L su btypes produced a receptor population with an intermediate sensitivity to GABA which was insensitive to loreclezole. These results suggest t hat functional GABARs can be formed that contain two different beta su bunit subtypes with properties different from receptors that contain o nly a single beta subtype and that the beta subunit subtypes influence the response of GABARs to GABA and to the allosteric modulator lorecl ezole. (C) 1998 published by Elsevier Science Ltd. All rights reserved .