Agonist-dependent single channel current and gating in [[alpha].sub.4][[beta].sub.2][delta] and [[alpha].sub.1][[beta].sub.2][[gamma].sub.2s] [GABA.sub.A] receptors

The family of [gamma]-aminobutyric acid type A receptors ([GABA.sub.A]Rs) mediates two types of inhibition in the mammalian brain. Phasic inhibition is mediated by synaptic [GABA.sub.A]Rs that are mainly comprised of [[alpha].sub.1], [[beta].sub.2], and [[gamma].sub.2] subunits, whereas tonic inhibition is mediated by extrasynaptic [GABA.sub.A]Rs comprised of [[alpha].sub.4/6], [[beta].sub.2], and [delta] subunits. We investigated the activation properties of recombinant [[alpha].sub.4][[beta].sub.2] [delta] and [[alpha].sub.1][[beta].sub.2][gamma].sub.2s] [GABA.sub.A]Rs in response to GABA and 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3 (2H)-one (THIP) using electrophysiological recordings from outside-out membrane patches. Rapid agonist application experiments indicated that THIP produced faster opening rates at [[alpha].sub.4][[beta].sub.2][delta] [GABA.sub.A]Rs ([beta] ~ 1600 [s.sup.-1]) than at [[alpha].sub.1][[beta].sub.2] [gamma].sub.2s] [GABA.sub.A]Rs ([beta] ~ 460 [s.sup.-1]), whereas GABA activated [[alpha].sub.1][[beta].sub.2][gamma].sub.2s] [GABA.sub.A]Rs more rapidly ([beta] ~1800 [s.sup.-1]) than [[alpha].sub.4][[beta].sub.2][delta] [GABA.sub.A]Rs ([beta] < 440 [s.sup.-1). Single channel recordings of [[alpha].sub.1] [[beta].sub.2][gamma].sub.2s] and [[alpha].sub.4][[beta].sub.2] [delta] [GABA.sub.A]Rs showed that both channels open to a main conductance state of ~25 pS at -70 mV when activated by GABA and low concentrations of THIE whereas saturating concentrations of THIP elicited ~36 pS openings at both channels. Saturating concentrations of GABA elicited brief (