P>Benzodiazepines act at the major isoforms of GABA type A receptors where they potentiate the current evoked by the agonist GABA. The underlying mechanism of this potentiation is poorly understood, but hypothesized to be related to the mechanism that links agonist binding to channel opening in these ligand activated ion channels. The loop F of the alpha(1) and the beta(2) subunit have been implicated in channel gating, and loop F of the gamma(2) subunit in the modulation by benzodiazepines. We have identified the conservative point mutation Y168F located N-terminally of loop F in the alpha(1) subunit that fails to affect agonist properties. Interestingly, it disrupts modulation by benzodiazepines, but leaves high affinity binding to the benzodiazepine binding site intact. Modulation by barbiturates and neurosteroids is also unaffected. Residue alpha(1)Y168 is not located either near the binding pockets for GABA, or for benzodiazepines, or close to the loop F of the gamma(2) subunit. Our results support the fact, that broader regions of ligand gated receptors are conformationally affected by the binding of benzodiazepines. We infer that also broader regions could contribute to signaling from GABA agonist binding to channel opening.