α1 and α6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABA A receptors containing the δ subunit

Abstract

GABA A receptor α subunit subtypes have distinct CNS distributions and confer different pharmacological and biophysical properties to αβγ receptor isoforms. However, the α subtype-dependent properties of αβδ receptor isoforms that may be targeted to extrasynaptic sites remain poorly understood. We investigated the properties of α1β3δ and α6β3δ receptor currents evoked by concentration jumps using a saturating GABA concentration (1 mM). α1β3δ receptor currents desensitized slowly, deactivated rapidly and displayed voltage-dependence only of peak amplitude. In contrast, α6β3δ receptor currents had voltage-dependent increased desensitization and slower deactivation, but did not show rectification. The neurosteroid THDOC (1 μM) enhanced α1β3δ more than α6β3δ currents, but increased the extent of desensitization and prolonged deactivation for both receptor isoforms. α1–α6 and α6–α1 chimeras (spliced in transmembrane domain 1) suggested that differences in deactivation rate and its voltage-dependence correlated with N-terminal domains, while the extent of desensitization and its voltage-dependence correlated with C-terminal domains. Both chimeras showed outward rectification. α1 subunit-like THDOC enhancement was observed with the α1–α6 chimera, but the α6–α1 chimera did not confer α6 subunit-like enhancement, suggesting that multiple α1 subunit domains contributed to neurosteroid efficacy. Thus, α subunit subtypes may regulate the kinetic and pharmacological properties of tonic neuronal inhibition.