Background: Gamma-aminobutyric acid type A (GABAA) 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 GABAA 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.
Results: The GABA sensitivites and effects of several positive modulators of GABAA 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.
Conclusion: The epsilon and theta subunits bring additional features to alpha3beta1 GABAA receptors. These receptor subtypes may constitute as novel drug targets in selected brain regions, e.g., in the brainstem locus coeruleus nuclei.