Alpha1 and alpha6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABA(A)...

GABA(A) receptor alpha subunit subtypes have distinct CNS distributions and confer different pharmacological and biophysical properties to alphabetagamma receptor isoforms. However, the alpha subtype-dependent properties of alphabetadelta receptor isoforms that may be targeted to extrasynaptic sites remain poorly understood. We investigated the properties of alpha1beta3delta and alpha6beta3delta receptor currents evoked by concentration jumps using a saturating GABA concentration (1 mM). alpha1beta3delta receptor currents desensitized slowly, deactivated rapidly and displayed voltage-dependence only of peak amplitude. In contrast, alpha6beta3delta receptor currents had voltage-dependent increased desensitization and slower deactivation, but did not show rectification. The neurosteroid THDOC (1 microM) enhanced alpha1beta3delta more than alpha6beta3delta currents, but increased the extent of desensitization and prolonged deactivation for both receptor isoforms. alpha1-alpha6 and alpha6-alpha1 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. alpha1 subunit-like THDOC enhancement was observed with the alpha1-alpha6 chimera, but the alpha6-alpha1 chimera did not confer alpha6 subunit-like enhancement, suggesting that multiple alpha1 subunit domains contributed to neurosteroid efficacy. Thus, alpha subunit subtypes may regulate the kinetic and pharmacological properties of tonic neuronal inhibition.