Biochem Pharmacol 2016 Mar 01;103:98-108. doi: 10.1016/j.bcp.2015.12.021.

High and low GABA sensitivity α4β2δ GABAA receptors are expressed in Xenopus laevis oocytes with divergent stoichiometries.

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GABAA receptors that contain the α4 and δ subunits are thought to be located extrasynaptically, mediating tonic currents elicited by low concentrations of GABA. These α4βδ receptors are modulated by neurosteroids and certain anesthetics, identifying them as important drug targets in research. However, pharmacological studies on these receptors have often yielded variable results, possibly due to the expression of receptors in different stoichiometries or arrangements. In this study, we injected different ratios of α4, β2 and δ cRNA into Xenopus oocytes and measured the sensitivity to GABA and DS2 activation of the resulting receptor populations. By creating a matrix of RNA injection ratios from stock RNA concentrations, we were able to compare the changes in pharmacology between injection ratios where the ratio of only one subunit was altered. We identified two distinct populations of receptors, the first with an EC50 value of approximately 100 nM to GABA, a low Hill slope of approximately 0.3 and substantial direct activation by DS2. The second population had an EC50 value of approximately 1 μM to GABA, a steeper Hill slope of 1 and little direct activation, but substantial potentiation, by DS2. The second population was formed with high α4 ratios and low β2 ratios, but altering the ratio of δ subunit injected had little effect. We propose that receptors with high sensitivity to GABA and direct activation by DS2 are the result of a greater number of β2 subunits being incorporated into the receptor.

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Species referenced: Xenopus laevis
Genes referenced: gabarap