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BMC Neurosci
2015 Mar 05;16:8. doi: 10.1186/s12868-015-0148-4.
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Pharmacological characterisation of murine α4β1δ GABAA receptors expressed in Xenopus oocytes.
Villumsen IS
,
Wellendorph P
,
Smart TG
.
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BACKGROUND: GABAA 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.
RESULTS: GABA activated concentration-dependent responses at α4β1δ and α4β1 receptors with EC50 values in the nanomolar to micromolar range, respectively. The divalent cations Zn(2+) and Cu(2+), and the β1-selective inhibitor salicylidine salicylhydrazide (SCS), inhibited GABA-activated currents at α4β1δ receptors. Surprisingly the α4β1 receptor demonstrated biphasic sensitivity to Zn(2+) inhibition that may reflect variable subunit stoichiometries with differing sensitivity to Zn(2+). The neurosteroid tetrahydro-deoxycorticosterone (THDOC) significantly increased GABA-initiated responses in concentrations above 30 nM for α4β1δ receptors.
CONCLUSIONS: With 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.
Figure 1.
Examples of GABA-activated currents recorded from cDNA-injected
Xenopus
oocytes expressing α4β1δ and α4β1 receptors. A, Representative membrane currents for α4β1δ receptors (upper panel) and α4β1 receptors (lower panel) in response to increasing concentrations of GABA. The oocytes were voltage clamped at -60 mV. B, GABA concentration response curves for α4β1δ (n = 6) and α4β1(n = 5) receptors. All data points represent means ± SEMs.
Figure 2.
Pharmacological modulation of GABA responses at α4β1δ receptors by various inhibitors and the neurosteroid, THDOC. A, Representative membrane currents showing inhibition of GABA (EC75) by 1 μM Zn2+ at α4β1 (upper) and α4β1δ (lower) receptors. B, Zn2+ concentration-inhibition relationships for α4β1 (n = 6) and α4β1δ (n = 6) receptors. C, Representative currents showing the degree of desensitization when activated by EC75 GABA in the absence (upper) and presence (lower) of 1 μM Cu2+. D, Cu2+ concentration-inhibition relationship for GABA EC75 desensitized responses at α4β1δ receptors by increasing concentrations of Cu2+ (n = 12). E, SCS concentration-inhibition relationship for GABA EC20 peak responses at α4β1δ receptors by increasing concentrations of SCS (n = 4). F, Response of α4β1δ receptors to increasing concentrations of THDOC co-applied with an EC7 GABA concentration. The responses were normalised to a preceding application of GABA EC7 in the absence of THDOC (n = 9). All data shown are means ± SEMs.
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