cAMP-producing chemogenetic and adenosine A2a receptor activation inhibits the inwardly rectifying potassium current in striatal projection neurons.
cAMP-producing chemogenetic and adenosine A2a receptor activation inhibits the inwardly rectifying potassium current in striatal projection neurons.
复制标题
产生 cAMP 的化学遗传学和腺苷 A2a 受体激活抑制纹状体投射神经元的内向整流钾电流。
DOI：
10.1016/j.neuropharm.2019.01.014
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发表时间：
2019
影响因子：
4.7
通讯作者：
Zhou,FM
中科院分区：
文献类型：
--
作者：
Wang,Qian;Zhou,FM
腺苷A2a受体(A2aRs)在D2中棘神经元(D2-MSN)高选择性表达，同时也表达高水平的多巴胺D2受体(D2Rs)。然而，A2aR活性如何影响D2-MSN兴奋性还没有确定，更不用说涉及的离子通道了。我们进行了两组实验，以确定潜在的A2aR激动剂对D2-MSN内在兴奋性的影响以及潜在的离子通道机制。首先，我们使用由设计药物(Gs-α)所独有的cAMP产生、G-DREADS/olf偶联的设计者受体(Gs-DREADD)来刺激cAMP激活A2aR。我们发现，Gs-DREADD的激活抑制了MSN兴奋性的关键调节因子--内向整流钾电流(KIR)，引起了去极化，增加了输入电阻，并显著增加了MSN的内在兴奋性，从而使去极化的输入诱发了更多的动作电位。其次，我们已经确定A2aR激动剂对D2-MSN的内在兴奋性和棘波放电产生同样的兴奋效应，尽管幅度低于Gs-DREADD激动剂；此外，在D2R拮抗剂存在的情况下，这些A2aR触发的兴奋效应是完整的。综上所述，这些结果清楚地表明，在纹状体D2-MSN中，A2aR的激活可以独立地抑制KIR，并增加固有的兴奋性、峰电位和神经递质输出；我们的结果还表明，Gs-DREADD可以作为神经递质受体的广泛有用的阳性对照，从而提高细胞内cAMP水平，从而有助于确定这些神经递质受体的细胞效应。
Adenosine A2a receptors (A2aRs) are highly and selectively expressed in D2-medium spiny neurons (D2-MSNs) that also express a high level of dopamine D2 receptors (D2Rs). However, it was not established how A2aR activity affects D2-MSN excitability, let alone the ion channels involved. We have performed two sets of experiments to determine the potential A2aR agonistic effects on D2-MSN intrinsic excitability and the underlying ion channel mechanism. First, we have used the cAMP-producing, Gαs/olfcoupled designer receptors exclusively activated by designer drug (Gs-DREADDs) to phenocopy cAMP-stimulating A2aR activation. We found that activation of Gs-DREADD inhibited the inwardly rectifying potassium current (Kir)–a key regulator of MSN excitability, caused a depolarization, increased input resistance, and substantially increased the intrinsic excitability of MSNs such that depolarizing inputs evoked many more action potentials. Second, we have determined that A2aR agonism produced these same excitatory effects on D2-MSN intrinsic excitability and spike firing, although at lower magnitudes than those induced by Gs-DREADD activation; furthermore, these A2aR-triggered excitatory effects were intact in the presence of a D2R antagonist. Taken together, these results clearly establish that in striatal D2-MSNs, A2aR activation can independently inhibit Kir and increase intrinsic excitability and spike and neurotransmitter output; our results also indicate that Gs-DREADD can serve as a broadly useful positive control for neurotransmitter receptors that increase intracellular cAMP levels and hence facilitate the determination of the cellular effects of these neurotransmitter receptors.