Neurosteroids Shift Partial Agonist Activation of GABAAReceptor Channels from Low- to High-Efficacy Gating Patterns

Abstract

Although GABA activates synaptic (αβγ) GABA_Areceptors with high efficacy, partial agonist activation of αβγ isoforms and GABA activation of the primary extrasynaptic (αβδ) GABA_Areceptors are limited to low-efficacy activity, characterized by minimal desensitization and brief openings. The unusual sensitivity of αβδ receptor channels to neurosteroid modulation prompted investigation of whether this high sensitivity was dependent on the δ subunit or the low-efficacy channel function that it confers. We show that the isoform specificity (αβδ > αβγ) of neurosteroid modulation could be reversed by conditions that reversed isoform-specific activity modes, including the use of β-alanine to achieve increased efficacy with αβδ receptors and taurine to render αβγ receptors low efficacy. We suggest that neurosteroids preferentially enhance low-efficacy GABA_Areceptor activity independent of subunit composition. Allosteric conversion of partial to full agonism may be a general mechanism for reversibly scaling the efficacy of GABA_Areceptors to endogenous partial agonists.