GABA activates different types of chloride-conducting receptor-ionophore complexes in a dose-dependent manner

We report here evidence for 3 new subtypes (alpha 1, alpha 2 and beta) of type-A GABA receptor-channel complexes that conduct chloride ions. The chloride current, ICl, was isolated in the frog sensory neuron by a combination of voltage clamp and internal perfusion. Analysis of the variance of GABA-induced ICl fluctuations shows that the channel population N decreases exponentially with single-channel conductance gamma in such a way that alpha 2 less than alpha 1 less than beta for gamma and alpha 2 much greater than alpha 1 greater than beta for N, and that the population-rank plot fits Zipf's law. Various aspects of the GABA-induced ICl are understood from dose-dependent activation and inactivation of these functionally distinct receptor-channel types. The steady-state ICl is mediated by alpha 1 at low but by beta units at high GABA concentrations, and the pronounced ICl peak at intermediate and high doses reflects the desensitization of alpha 1 and alpha 2 receptors, respectively. Picrotoxin blocks alpha 1 and alpha 2 and has no effect on beta channels. Patch-clamp recordings indicate two distinct classes of GABA-gated chloride conductances that appear to correspond to the alpha 1 and beta types. The presence of these different ICl components explains why the dose-response relationship cannot be fitted well by a single Hill equation; the fitting requires a synthesis of 3 suitable Hill equations.