Activation of alpha-2 adrenergic receptors stimulates GABA release by astrocytes
Activation of alpha-2 adrenergic receptors stimulates GABA release by astrocytes
复制标题
DOI：
10.1002/glia.23763
复制
发表时间：
2020-06-01
期刊：
影响因子：
6.2
通讯作者：
Kosenkov, Artem M.
中科院分区：
文献类型：
--
作者：
Gaidin, Sergei G.;Zinchenko, Valery P.;Kosenkov, Artem M.
去甲肾上腺素是海马中的关键神经递质之一，但其在神经胶质网络功能中的作用仍不清楚。在这里，我们表明，去甲肾上腺素抑制氯化铵诱导的海马神经元胞内钙离子浓度（[Ca 2 +]（i））的振荡。我们发现去甲肾上腺素对铵诱导的[Ca ~（2+）]（i）振荡的抑制作用是通过激活α-2肾上腺素能受体介导的。此外，UK 14，304（α-2肾上腺素能受体激动剂）在少数星形胶质细胞中引起双相[Ca 2 +]（i）升高。这种升高包括由G（i beta gamma）亚基介导的初始快速峰形[Ca 2 +]（i）升高和随后PLC诱导的Ca 2+从内部储存的动员，以及由Ca 2+从细胞外介质通过储存操作和TRPC 3通道内流介导的平台期。我们显示星形胶质细胞中的Ca 2+反应与神经元中[Ca 2 +]（i）振荡的抑制之间的相关性。UK 14，304的抑制作用在G（β-γ）信号传导抑制剂gallein存在下消失。反过来，在PLC抑制剂存在下应用激动剂会降低神经元中[Ca 2 +]（i）振荡的频率和幅度，但不会抑制它们。在GABA（A）受体拮抗剂荷包牡丹碱的存在下观察到相同的效果。我们证明，UK 14，304应用增加神经元中缓慢外向氯电流的频率和幅度，表明星形胶质细胞释放GABA。因此，我们的研究结果表明，星形胶质细胞α-2肾上腺素能受体的激活刺激GABA释放星形胶质细胞通过G（β γ）亚基相关的信号通路，有助于抑制神经元的活动。
Norepinephrine is one of the key neurotransmitters in the hippocampus, but its role in the functioning of the neuroglial networks remains unclear. Here we show that norepinephrine suppresses NH4Cl-induced oscillations of the intracellular Ca2+ concentration ([Ca2+](i)) in hippocampal neurons. We found that the inhibitory effect of norepinephrine against ammonium-induced [Ca2+](i) oscillations is mediated by activation of alpha-2 adrenergic receptors. Furthermore, UK 14,304, an agonist of alpha-2 adrenergic receptors, evokes a biphasic [Ca2+](i) elevation in a minor population of astrocytes. This elevation consists of an initial fast, peak-shaped [Ca2+](i) rise, mediated by G(i beta gamma) subunit and subsequent PLC-induced mobilization of Ca2+ from internal stores, and a plateau phase, mediated by a Ca2+ influx from the extracellular medium through store-operated and TRPC3 channels. We show the correlation between the Ca2+ response in astrocytes and suppression of [Ca2+](i) oscillations in neurons. The inhibitory effect of UK 14,304 is abolished in the presence of gallein, an inhibitor of G(beta gamma)-signaling. In turn, application of the agonist in the presence of the PLC inhibitor decreases the frequency and amplitude of [Ca2+](i) oscillations in neurons but does not suppress them. The same effect is observed in the presence of bicuculline, a GABA(A) receptor antagonist. We demonstrate that UK 14,304 application increases the frequency and amplitude of slow outward chloride currents in neurons, indicating the release of GABA by astrocytes. Thus, our findings indicate that the activation of astrocytic alpha-2 adrenergic receptors stimulates GABA release from astrocytes via G(i beta gamma) subunit-associated signaling pathway, contributing to the suppression of neuronal activity.