PNU-107484A with α isoform-dependent functional changes in αxβ2γ2 subtypes of rat recombinant GABA(A) receptors

Abstract

1. We discovered a novel γ-aminobutyric acid(A) (GABA(A)) receptor ligand displaying seemingly opposite functionalities, depending on the a isoform of the αxβ2γ2 subtypes. PNU-107484A enhanced GABA-induced Cl- currents in the α1β2γ2 subtype, but inhibited the currents in the α3β2γ2 and α6β2γ2 subtypes, and its half-maximal concentrations in the subtypes were 3.1 ± 0.5, 4.2 ± 1, and 3.5 ± 0.2 μM, respectively, without showing much dependency on a isoforms. 2. In the α1β2 subtype, the drug at concentrations up to 40 μM showed no effect on GABA-induced Cl- currents, suggesting the requirement of the γ subunit for its action. 3. PNU-107484A behaved like a positive allosteric modulator of the α1β2γ2 subtype with its binding site distinct from those for benzodiazepines, barbiturates and neurosteroids. With the α3β2γ2 subtype, the drug behaved like a non-competitive inhibitor of GABA, thus blocking Cl- currents by GABA alone or in the presence of pentobarbitone and neurosteroids. 4. It appears that PNU-107484A is a unique GABA(A) receptor ligand with a isoform-dependent functionalities, which may provide a basis for development of a isoform-selective ligands, and it could be useful as a probe to investigate the physiological roles of the various a isoform subtypes.