Gamma-aminobutyric acid type A
(GABA_A) receptors provide the main inhibitory control in the brain.
Their heterogeneity may make it possible to precisely target drug
effects to selected neuronal populations. In situ hybridization using
rat brain sections has revealed a unique expression of GABA_A receptor
epsilon and theta subunit transcripts in the locus coeruleus, where they
are accompanied at least by alpha3, alpha2, beta1 and beta3 subunits.
Here, we studied the pharmacology of the human alpha3beta1,
alpha3beta1epsilon, alpha3beta1theta and alpha3beta1epsilontheta
receptor subtypes expressed in Xenopus oocytes and compared them with
the gamma2 subunit-containing receptors.

The
GABA sensitivites and effects of several positive modulators of GABA_A
receptors were studied in the absence and the presence of EC₂₅ GABA
using the two-electrode voltage-clamp method. We found 100-fold
differences in GABA sensitivity between the receptors,
alpha3beta1epsilon subtype being the most sensitive and
alpha3beta1gamma2 the least sensitive. Also gaboxadol dose-response
curves followed the same sensitivity rank order, with EC₅₀ values being
72 and 411 microM for alpha3beta1epsilon and alpha3beta1gamma2 subtypes,
respectively. In the presence of EC₂₅ GABA, introduction of the epsilon
subunit to the receptor complex resulted in diminished modulatory
effects by etomidate, propofol, pregnanolone and flurazepam, but not by
pentobarbital. Furthermore, the alpha3beta1epsilon subtype displayed
picrotoxin-sensitive spontaneous activity. The theta subunit-containing
receptors were efficiently potentiated by the anesthetic etomidate,
suggesting that theta subunit could bring the properties of beta2 or
beta3 subunits to the receptor complex.

The
epsilon and theta subunits bring additional features to alpha3beta1
GABA_A receptors. These receptor subtypes may constitute as novel drug
targets in selected brain regions, e.g., in the brainstem locus
coeruleus nuclei.