Bicarbonate efflux via GABA(A) receptors depolarizes membrane potential and inhibits two-pore domain potassium channels of astrocytes in rat hippocampal slices.
Bicarbonate efflux via GABA(A) receptors depolarizes membrane potential and inhibits two-pore domain potassium channels of astrocytes in rat hippocampal slices.
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作者：
Ma, Bao-Feng;Xie, Min-Jie;Zhou, Min
越来越多的证据表明离子型γ-氨基丁酸受体（GABAA-R）在星形胶质细胞中有功能性表达。然而，关于星形胶质细胞内Cl−浓度（[Cl−]i）和阴离子选择性GABAA-R在星形胶质细胞中的功能作用仍然存在争议。在大鼠海马CA 1区星形胶质细胞的短杆菌肽穿孔贴片记录中，GABA和GABAA-R特异性激动剂THIP使星形胶质细胞膜电位（Vm）去极化，THIP诱导的电流在−75.3至−78.3 mV之间的电压下逆转，对应于3.1 - 3.9 mM的[Cl−]i，有利于Cl−阴离子在星形胶质细胞膜上的被动分布。进一步的分析表明，GABAA-R诱导的Vm去极化归因于HCO 3 −流出，而被动分布的Cl−不介导导致不变或超极化Vm的Cl-净通量或内流。除了快速激活的GABAA-R电流成分外，GABA和THIP还在63%的星形胶质细胞中诱导延迟内向电流（DIC）。DIC在激动剂停药后变得明显，并随着激动剂应用时间或浓度的增加而增强。星形胶质细胞双孔结构域K+通道（K2 Ps），特别是TWIK-1，似乎是DIC的基础，因为1）HCO 3 −流出导致的酸性细胞内pH抑制TWIK-1; 2）DIC保留在抑制常规K+通道的Cs+记录溶液中; 3）DIC被1 mM奎宁完全抑制，但不被其他阳离子/阴离子通道的阻断剂抑制。总之，HCO 3 −通过激活的GABAA-R流出使星形胶质细胞Vm去极化，并通过细胞内酸化诱导K2 Ps K+通道的延迟抑制。
Increasing evidence indicates the functional expression of ionotropic γ-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 to −78.3 mV, corresponding to a [Cl−]i of 3.1 – 3.9 mM that favors a passive distribution of Cl− anions across astrocyte membrane. Further analysis showed that GABAA-R induced Vm depolarization is ascribed to HCO3− efflux, while a passively distributed Cl− mediates 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.
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