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Allosteric modulation of GABAA receptors by extracellular ATP

机译：细胞外ATP对GABA A 受体的变构调节

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Background The γ-aminobutyric acid type A receptor (GABAAR) is the primary receptor mediating fast synaptic inhibition in the brain and plays a critical role in modulation of neuronal excitability and neural networks. Previous studies have demonstrated that ATP and its nucleotide analogs may regulate the function of GABAARs via Ca2+-dependent intracellular mechanisms, which require activation of purinergic 2 (P2) receptors or cross-talk between two receptors. Results Here, we report a potentiation of GABAARs by extracellular ATP via a previously un-recognized allosteric mechanism. Using cultured hippocampal neurons as well as HEK293 cells transiently expressing GABAARs, we demonstrate that extracellular ATP potentiates GABAAR mediated currents in a dose-dependent manner with an EC50 of 2.1?±?0.2 mM. The potentiation was mediated by a postsynaptic mechanism that was not dependent on activation of either ecto-protein kinase or P2 receptors. Single channel recordings from cell-free excised membrane patches under outside-out mode or isolated membrane patches under cell-attached mode suggest that the ATP modulation of GABA currents is achieved through a direct action of ATP on the channels themselves and manifested by increasing the single channel open probability without alteration of its conductance. Moreover, this ATP potentiation of GABAAR could be reconstituted in HEK293 cells that transiently expressed recombinant rat GABAARs. Conclusions Our data strongly suggest that extracellular ATP allosterically potentiates GABAAR-gated chloride channels. This novel mode of ATP-mediated modulation of GABAARs may play an important role in regulating neuronal excitability and thereby in fine-tuning the excitation-inhibition balance under conditions where a high level of extracellular ATP is ensured.
机译：背景技术γ-氨基丁酸A型受体（GABAAR）是介导大脑中快速突触抑制的主要受体，在调节神经元兴奋性和神经网络中起关键作用。先前的研究表明，ATP及其核苷酸类似物可能通过依赖Ca2 +的细胞内机制调节GABAAR的功能，这需要激活嘌呤能2（P2）受体或两个受体之间的串扰。结果在这里，我们报告了通过先前无法识别的变构机制，通过细胞外ATP增强GABAAR的作用。使用培养的海马神经元以及瞬时表达GABAAR的HEK293细胞，我们证明细胞外ATP以剂量依赖性方式增强GABAAR介导的电流，EC50为2.1？±？0.2 mM。增强作用是由突触后机制介导的，该机制不依赖于外在蛋白激酶或P2受体的激活。从外向内模式下的无细胞切除膜片或在细胞附着模式下的离体膜片的单通道记录表明，GABA电流的ATP调节是通过ATP对通道本身的直接作用来实现的，并通过增加单通道开放概率而不会改变其电导。此外，GABAAR的这种ATP增强作用可以在瞬时表达重组大鼠GABAAR的HEK293细胞中重建。结论我们的数据强烈表明，细胞外ATP会变构地增强GABAAR门控的氯离子通道。这种新型的ATP介导的GABAARs调节模式可能在调节神经元兴奋性中起重要作用，从而在确保高水平胞外ATP的条件下微调兴奋抑制平衡。

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