Abstract
We discovered a novel γ-aminobutyric acidA (GABAA) 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 μM, respectively, without showing much dependency on α isoforms.
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.
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 GABAA 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.
Keywords: GABAA, GABA-induced Cl− currents, PNU-107484A, α-isoform-selective ligand
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