Abstract
BackgroundGABAA receptor subunit composition has a profound effect on the receptor’s physiological and pharmacological properties. The receptor β subunit is widely recognised for its importance in receptor assembly, trafficking and post-translational modifications, but its influence on extrasynaptic GABAA receptor function is less well understood. Here, we examine the pharmacological properties of a potentially native extrasynaptic GABAA receptor that incorporates the β1 subunit, specifically composed of α4β1δ and α4β1 subunits.ResultsGABA activated concentration-dependent responses at α4β1δ and α4β1 receptors with EC50 values in the nanomolar to micromolar range, respectively. The divalent cations Zn2+ and Cu2+, and the β1-selective inhibitor salicylidine salicylhydrazide (SCS), inhibited GABA-activated currents at α4β1δ receptors. Surprisingly the α4β1 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 α4β1δ receptors.ConclusionsWith this study we report the first pharmacological characterisation of various GABAA receptor ligands acting at murine α4β1δ GABAA 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 α4β1δ receptors. We consider the likelihood that the α4β1δ receptor may play a role as an extrasynaptic GABAA receptor in the nervous system.
Highlights
GABAA receptor subunit composition has a profound effect on the receptor’s physiological and pharmacological properties
Few studies have investigated the properties of either human [25,26,27] or murine [23,28] recombinant α4β1δ receptors, and none of these have fully addressed the characterisation of classic GABAA receptor ligands. In these studies, interesting pharmacological differences between murine and human α4β1δ receptors are manifest: human receptors expressed in Xenopus oocytes [25] are constitutively active and display a γ-aminobutyric acid (GABA) EC50 in the mid-nanomolar range whereas the rat/ mouse receptor expressed in oocytes or human embryonic kidney 293 (HEK293) cells display low-micromolar sensitivity towards activation by GABA [23,28]. To address this apparent speciesdependent pharmacology and to address the effects of commonly used GABA receptor ligands, we report the pharmacological profiles for several GABAA receptor ligands at recombinant murine α4β1 and α4β1δ receptors expressed in Xenopus laevis oocytes
In this study we investigated the pharmacological profiles of several GABAA receptor ligands at murine α4β1δ receptors
Summary
GABAA receptor subunit composition has a profound effect on the receptor’s physiological and pharmacological properties. We examine the pharmacological properties of a potentially native extrasynaptic GABAA receptor that incorporates the β1 subunit, composed of α4β1δ and α4β1 subunits. GABAA receptors are pentameric ligand-gated ion channels that mediate phasic and tonic inhibition in the central nervous system [1]. The co-assembly of combinations of 19 different subunits (α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3) into homo- or hetero-pentameric receptors results in multiple different GABAA receptor isoforms with different function, pharmacology and neuronal location [2,3,4]. Receptors incorporating α1, α2 or α3 subunits most commonly assemble with β and γ subunits, and are generally located at the synapse where they mediate phasic inhibition; whereas α4 and α6-containing receptors assemble with β and δ subunits, and are found extrasynaptically, mediating tonic inhibition [13]. It has been suggested that δ can co-assemble with α1 subunits in hippocampal interneurons [14,15]
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