PNU-107484A WITH ALPHA-ISOFORM-DEPENDENT FUNCTIONAL-CHANGES IN ALPHA-X-BETA-2-GAMMA-2 SUBTYPES OF RAT RECOMBINANT GABA(A) RECEPTORS

1 We discovered a novel gamma-aminobutyric acid(A) (GABA(A)) receptor ligand displaying seemingly opposite functionalities, depending on the alpha isoform of the alpha x beta 2 gamma 2 subtypes. PNU-107484A enh anced GABA-induced Cl- currents in the alpha 1 beta 2 gamma 2 subtype, but inhibited the currents in the alpha 3 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 subtypes, and its half-maximal concentrations in the su btypes were 3.1+/-0.5, 4.2+/-1, and 3.5+/-0.2 mu M, respectively, with out showing much dependency on alpha isoforms. 2 In the alpha 1 beta 2 subtype, the drug at concentrations up to 40 mu M showed no effect on GABA-induced Cl- currents, suggesting the requirement of the gamma su bunit for its action. 3 PNU-107484A behaved like a positive allosteric modulator of the alpha 1 beta 2 gamma 2 subtype with its binding site distinct from those for benzodiazepines, barbiturates and neurosteroi ds. With the alpha 3 beta 2 gamma 2 subtype, the drug behaved like a n on-competitive inhibitor of GABA, thus blocking Cl- currents by GABA a lone or in the presence of pentobarbitone and neurosteroids. 4 It appe ars that PNU-107484A is a unique GABA(A) receptor ligand with alpha is oform-dependent functionalities, which may provide a basis for develop ment of alpha isoform-selective ligands, and it could be useful as a p robe to investigate the physiological roles of the various alpha isofo rm subtypes.