Bicarbonate efflux via GABAA receptors depolarizes membrane potential and inhibits two-pore domain potassium channels of astrocytes in rat hippocampal slices

Increasing evidence indicates the functional expression of ionotropic gamma-aminobutyric acid receptor (GABAA-R) in astrocytes. However, it remains controversial in regard to the intracellular Cl- concentration ([Cl-]i) and the functional role of anion-selective GABAA-R in astrocytes. In gramicidin perforated-patch recordings from rat hippocampal CA1 astrocytes, GABA and GABAA-R-specific agonist THIP depolarized astrocyte membrane potential (Vm), and the THIP-induced currents reversed at the voltages between -75.3 and -78.3 mV, corresponding to a [Cl-]i of 3.13.9 mM that favored a passive distribution of Cl- anions across astrocyte membrane. Further analysis showed that GABAA-R-induced Vm depolarization was ascribed to HCO3- efflux, while a passively distributed Cl- mediated no net flux or influx of Cl- that leads to an unchanged or hyperpolarized Vm. In addition to a rapidly activated GABAA-R current component, GABA and THIP also induced a delayed inward current (DIC) in 63% of astrocytes. The DIC became manifest after agonist withdrawal and enhanced in amplitude with increasing agonist application duration or concentrations. Astrocytic two-pore domain K+ channels (K2Ps), especially TWIK-1, appeared to underlie the DIC, because (1) acidic intracellular pH, as a result of HCO3- efflux, inhibited TWIK-1, (2) the DIC remained in the Cs+ recording solutions that inhibited conventional K+ channels, and (3) the DIC was completely inhibited by 1 mM quinine but not by blockers for other cation/anion channels. Altogether, HCO3- efflux through activated GABAA-R depolarizes astrocyte Vm and induces a delayed inhibition of K2Ps K+ channels via intracellular acidification. (c) 2012 Wiley Periodicals, Inc.