The wake-promoting transmitter histamine preferentially enhances α-4 subunit-containing GABAA receptors.
The wake-promoting transmitter histamine preferentially enhances α-4 subunit-containing GABAA receptors.
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DOI：
10.1016/j.neuropharm.2011.05.020
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Fisher JL
中科院分区：
文献类型：
--
作者：
Bianchi MT;Clark AG;Fisher JL
组胺是一种重要的促醒神经递质，可激活七跨膜G蛋白偶联组胺受体。然而，组胺表现出目标混杂性，包括与结构无关的谷氨酸（NMDA）和GABAA受体通道的直接相互作用。以前的工作表明，组胺增强了重组GABAA受体亚型的活性，通常发现在突触位置，虽然共同释放组胺和GABA是不知道发生在体内。在这里，我们使用膜片钳记录的各种重组GABAA受体亚型（α1-6，β1-3，γ1-3，δ），以测试的假设，组胺可能会显示亚基偏好在低浓度的GABA（突触外）条件。我们发现，组胺增强了整个细胞的GABA的所有测试的亚基组合的反应。然而，α4β3和α4β3X亚型的增强幅度最大（约为EC 10 GABA诱发电流的400%），其中X可以是γ或δ。相比之下，组胺（1 mM）对1 mM GABA短暂（5 ms）脉冲后延长α4β3γ2受体失活的影响较小。这些发现表明，GABA-组胺串扰可能优先发生在低GABA浓度下，理论上可能是抑制性的（通过增强紧张性抑制），直接兴奋性的（通过增强突触前GABA能信号传导），或间接兴奋性的（通过抑制GABA能中间神经元）。
Histamine is an important wake-promoting neurotransmitter that activates seven-transmembrane G-protein coupled histamine receptors. However, histamine demonstrates target promiscuity, including direct interaction with the structurally unrelated glutamate (NMDA) and GABAA receptor channels. Previous work showed that histamine enhances the activity of recombinant GABAA receptor isoforms typically found in synaptic locations, although co-release of histamine and GABA is not known to occur in vivo. Here we used patch clamp recordings of various recombinant GABAA receptor isoforms (α1-6, β1-3, γ1-3, δ) to test the hypothesis that histamine might show subunit preference under low GABA concentration (extrasynaptic) conditions. We found that histamine potentiated the whole cell responses to GABA for all tested subunit combinations. However, the magnitude of enhancement was largest (~400% of EC10 GABA-evoked currents) with α4β3 and α4β3X isoforms, where X could be γ or δ. In contrast, histamine (1mM) had small effects on prolonging deactivation of α4β3γ2 receptors following brief (5ms) pulses of 1mM GABA. These findings suggest GABA-histamine cross-talk may occur preferentially at low GABA concentrations, which could theoretically be inhibitory (via enhancing tonic inhibition), directly excitatory (via enhancing presynaptic GABAergic signaling), or indirectly excitatory (via inhibiting GABAergic interneurons).