The cDNAs encoding alpha 5 and gamma 2L subunit subtypes of the gamma-
aminobutyric acid (GABA) type A receptor (GABAR) were transfected into
L929 cells together with cDNAs encoding either the beta 1, beta 2, or
beta 3 subunit subtype. Properties of expressed recombinant alpha 5 b
eta X gamma 2L (where X = 1, 2, or 3) GABARs were studied with the use
of whole-cell, patch-clamp techniques. In cells voltage-clamped at -7
0 mV with equivalent bath and pipette chloride concentrations, the app
lication of GABA produced a concentration-dependent inward chloride cu
rrent with all three alpha 5 beta X gamma 2L isoforms. Minimal or no r
esponses were recorded from cells transfected with only two subunit cD
NAs, demonstrating that all three subunits were required for functiona
l receptor assembly in these cells. The GABA concentration producing a
half-maximal current was similar for beta 2 and beta 3 subtype-contai
ning receptors (6 mu M) but higher for beta 1 subtype-containing recep
tors (26 mu M). alpha 5 beta 3 gamma 2L receptors were zinc and diazep
am sensitive but zolpidem insensitive. In response to low GABA concent
rations, beta 1 and beta 3 subtype-containing receptors showed outward
rectification of the current-voltage relationship, whereas current-vo
ltage responses of beta 2 subtype-containing receptors were relatively
linear. Likewise, al high GABA concentrations, beta 1 and beta 3 subt
ype-containing receptors showed less desensitization at positive than
at negative membrane potentials. beta 2 subtype-containing receptors d
isplayed faster desensitization at depolarized potentials. These volta
ge-dependent properties were characteristic of alpha 5 but not alpha 1
or alpha 6 subtype-containing receptors and were similar to responses
recorded from hippocampal CA1 pyramidal neurons. Based on the pharmac
ological and biophysical similarities to hippocampal GABAR responses,
the alpha 5 beta 3 gamma 2L isoform could represent a native GABAR sub
type.