大鼠纹状体放射性标记乙酰胆碱合成和释放的评价,Journal of Neurochemistry

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大鼠纹状体放射性标记乙酰胆碱合成和释放的评价
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2021-12-08 , DOI: 10.1111/jnc.15556
Ikunobu Muramatsu ₁ , Junsuke Uwada ₁ , Kazuyasu Chihara ₂ , Kiyonao Sada ₂ , Mao-Hsien Wang ₂ , Takashi Yazawa ₃ , Takanobu Taniguchi ₃ , Takaharu Ishibashi ₁ , Takayoshi Masuoka ₁

Affiliation

胆碱能传递是认知和运动等高级大脑功能的基础。为了阐明在中枢神经系统中维持和调节乙酰胆碱 (ACh) 释放的过程，研究了大鼠纹状体节段中 [ ^{3 H] 胆碱的摄取以及 [}³ H] ACh 的随后合成和释放。^{与 [ 3} H] 胆碱一起孵育可通过高亲和力胆碱转运蛋白 1 引发有效吸收，从而导致 [ ³ H] 胆碱和 [ ³ H]ACh 的积累。然而，在抑制 ACh 酯酶 (AChE) 后，与 [ ³ H] 胆碱孵育主要导致 [ ³H]乙酰胆碱。电刺激和 KCl 去极化选择性地释放 [ ³ H]ACh 而不是 [ ³ H]胆碱。[ ³ H]ACh 释放在重复刺激后逐渐下降，而在 AChE 抑制下释放可重现。[ ³ H]ACh 释放在用 vesamicol（一种囊泡 ACh 转运蛋白抑制剂）处理后被消除。这些结果表明，可释放的乙酰胆碱不断从细胞质中补充到可释放的胆碱能囊泡池中，以维持胆碱能传递。河豚毒素消除了电刺激引起的[ ³ H]ACh释放，而KCl诱导的[ 3 H]ACh释放在很大程度上具有抗性。ACh 释放量为 Ca ²⁺依赖于两种刺激之间的对 N 型和 P 型 Ca ²⁺通道毒素（分别为 ω-芋螺毒素 GVIA 和 ω-agatoxin IVA）的敏感性并表现出略微不同的敏感性。[ ³ H]ACh 释放受 M2 毒蕈碱和 D2 多巴胺能受体的负调控。目前的结果表明，抑制胆碱能神经元内的 AChE 和抑制 ACh 释放的突触前负调节有助于维持和促进胆碱能传递，为胆碱能功能障碍相关疾病的治疗开发提供潜在有用的线索，除了抑制突触间隙 AChE。

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Evaluation of radiolabeled acetylcholine synthesis and release in rat striatum

Cholinergic transmission underlies higher brain functions such as cognition and movement. To elucidate the process whereby acetylcholine (ACh) release is maintained and regulated in the central nervous system, uptake of [³H]choline and subsequent synthesis and release of [³H]ACh were investigated in rat striatal segments. Incubation with [³H]choline elicited efficient uptake via high-affinity choline transporter-1, resulting in accumulation of [³H]choline and [³H]ACh. However, following inhibition of ACh esterase (AChE), incubation with [³H]choline led predominantly to the accumulation of [³H]ACh. Electrical stimulation and KCl depolarization selectively released [³H]ACh but not [³H]choline. [³H]ACh release gradually declined upon repetitive stimulation, whereas the release was reproducible under inhibition of AChE. [³H]ACh release was abolished after treatment with vesamicol, an inhibitor of vesicular ACh transporter. These results suggest that releasable ACh is continually replenished from the cytosol to releasable pools of cholinergic vesicles to maintain cholinergic transmission. [³H]ACh release evoked by electrical stimulation was abolished by tetrodotoxin, but that induced by KCl was largely resistant. ACh release was Ca²⁺ dependent and exhibited slightly different sensitivities to N- and P-type Ca²⁺ channel toxins (ω-conotoxin GVIA and ω-agatoxin IVA, respectively) between both stimuli. [³H]ACh release was negatively regulated by M2 muscarinic and D2 dopaminergic receptors. The present results suggest that inhibition of AChE within cholinergic neurons and of presynaptic negative regulation of ACh release contributes to maintenance and facilitation of cholinergic transmission, providing a potentially useful clue for the development of therapies for cholinergic dysfunction-associated disorders, in addition to inhibition of synaptic cleft AChE.

更新日期：2022-01-20

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