Pharmacological characterisation of murine α4β1δ GABAA receptors expressed in Xenopus oocytes

Background: GABA(A) receptor subunit composition has a profound effect on the receptor's physiological and pharmacological properties. The receptor beta subunit is widely recognised for its importance in receptor assembly, trafficking and post-translational modifications, but its influence on extrasynaptic GABA(A) receptor function is less well understood. Here, we examine the pharmacological properties of a potentially native extrasynaptic GABA(A) receptor that incorporates the beta 1 subunit, specifically composed of alpha 4 beta 1 delta and alpha 4 beta 1 subunits. Results: GABA activated concentration-dependent responses at alpha 4 beta 1 delta and alpha 4 beta 1 receptors with EC50 values in the nanomolar to micromolar range, respectively. The divalent cations Zn2+ and Cu2+, and the beta 1-selective inhibitor salicylidine salicylhydrazide (SCS), inhibited GABA-activated currents at alpha 4 beta 1 delta receptors. Surprisingly the alpha 4 beta 1 receptor demonstrated biphasic sensitivity to Zn2+ inhibition that may reflect variable subunit stoichiometries with differing sensitivity to Zn2+. The neurosteroid tetrahydro-deoxycorticosterone (THDOC) significantly increased GABA-initiated responses in concentrations above 30 nM for alpha 4 beta 1 delta receptors. Conclusions: With this study we report the first pharmacological characterisation of various GABA(A) receptor ligands acting at murine alpha 4 beta 1 delta GABA(A) receptors, thereby improving our understanding of the molecular pharmacology of this receptor isoform. This study highlights some notable differences in the pharmacology of murine and human alpha 4 beta 1 delta receptors. We consider the likelihood that the alpha 4 beta 1 delta receptor may play a role as an extrasynaptic GABA(A) receptor in the nervous system.