Saturation and self-inhibition of rat hippocampal GABA(A) receptors at high GABA concentrations.

Current responses to ultrafast gamma-aminobutyric acid (GABA) applications were recorded from excised patches in rat hippocampal neurons to study the gating properties of GABA(A) receptors at GABA concentrations close to saturating ones and higher. The amplitude of currents saturated at approximately 1 mm, while the onset rate of responses reached saturation at 4-6 mm GABA. At high GABA concentrations (> 10 mm), the amplitude of current responses was reduced in a dose-dependent manner with a half-blocking GABA concentration of approximately 50 mm. The peak reduction at high GABA doses was accompanied by a tendency to increase the steady-state to peak ratio. At concentrations higher than 30 mm, this effect took the form of a rebound current, i.e. during the prolonged GABA applications, the current firstly declined due to desensitization onset and then, instead of decreasing towards a steady-state value, clearly increased. Both the self-inhibition of GABA(A) receptors by high GABA doses and rebound were clearly voltage dependent, being larger at positive holding potentials. The fast desensitization component accelerated with depolarization at all saturating [GABA] tested. The rebound phenomenon indicates that the self-block of GABAA receptors is state dependent, and suggests that the sojourn in the desensitized conformation provides a 'rescue' from the block. We propose that high GABA concentrations inhibit the receptors by direct occlusion of the channel pore having no effect on the receptor gating.