| Abstrakt: |
1We 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.2In the α1β2 subtype, the drug at concentrations up to 40 μMshowed no effect on GABA‐induced Cl−currents, suggesting the requirement of the γ subunit for its action.3PNU‐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.4It appears that PNU‐107484A is a unique GABAAreceptor 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. |
Plný text