PNU‐107484A with α isoform‐dependent functional changes in α x β 2γ2 subtypes of rat recombinant GABA A receptors

We discovered a novel γ‐aminobutyric acid A (GABA A ) receptor ligand displaying seemingly opposite functionalities, depending on the α 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 μ M , respectively, without showing much dependency on α isoforms. In the α1β2 subtype, the drug at concentrations up to 40 μ M showed no effect on GABA‐induced Cl − currents, suggesting the requirement of the γ subunit for its action. 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. It appears that PNU‐107484A is a unique GABA A receptor ligand with α isoform‐dependent functionalities, which may provide a basis for development of α isoform‐selective ligands, and it could be useful as a probe to investigate the physiological roles of the various α isoform subtypes. British Journal of Pharmacology (1997) 122 , 821–824; doi: 10.1038/sj.bjp.0701450