Tyrosine phosphorylation differentially fine-tunes ionotropic and metabotropic responses of human α7 nicotinic acetylcholine receptor.
Tyrosine phosphorylation differentially fine-tunes ionotropic and metabotropic responses of human α7 nicotinic acetylcholine receptor.
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DOI：
10.1007/s00018-021-03853-3
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Bouzat C
中科院分区：
文献类型：
--
作者：
Chrestia JF;Bruzzone A;Esandi MDC;Bouzat C
α7 烟碱乙酰胆碱受体与神经系统、神经退行性和炎症性疾病有关。它既作为配体门控阳离子通道又作为神经元和非神经元细胞中的代谢受体发挥作用。由于蛋白质磷酸化是一种重要的细胞功能调节机制，因此需要破译酪氨酸磷酸化如何调节 α7 双重离子型/代谢型分子功能，以了解其在生理和病理过程中的不可或缺的作用。 ACh 引起的 α7 单通道活动表现为短暂的孤立的开口，很少表现为快速连续的少数开口的发作。通过抑制酪氨酸激酶来减少磷酸化会增加激活发作的持续时间和频率，而抑制磷酸酶则具有相反的效果。去除 α7 胞内结构域的两个酪氨酸残基概括了酪氨酸激酶抑制介导的作用。无酪氨酸突变受体表现出更长的激活持续时间、降低的脱敏率以及从脱敏中显着更快的恢复，表明磷酸化通过有利于脱敏状态来降低α7通道活性。然而，突变受体无法响应 α7 激动剂而触发 ERK1/2 磷酸化。因此，虽然酪氨酸磷酸化对于 α7 触发的 ERK 通路是绝对必需的，但它会对 α7 离子活性产生负调节。总体而言，磷酸化/去磷酸化事件微调由 α7 激活介导的整合细胞反应，从而对 α7 胆碱能信号传导产生广泛影响。
The α7 nicotinic acetylcholine receptor is involved in neurological, neurodegenerative, and inflammatory disorders. It operates both as a ligand-gated cationic channel and as a metabotropic receptor in neuronal and non-neuronal cells. As protein phosphorylation is an important cell function regulatory mechanism, deciphering how tyrosine phosphorylation modulates α7 dual ionotropic/metabotropic molecular function is required for understanding its integral role in physiological and pathological processes. α7 single-channel activity elicited by ACh appears as brief isolated openings and less often as episodes of few openings in quick succession. The reduction of phosphorylation by tyrosine kinase inhibition increases the duration and frequency of activation episodes, whereas the inhibition of phosphatases has the opposite effect. Removal of two tyrosine residues at the α7 intracellular domain recapitulates the effects mediated by tyrosine kinase inhibition. The tyrosine-free mutant receptor shows longer duration-activation episodes, reduced desensitization rate and significantly faster recovery from desensitization, indicating that phosphorylation decreases α7 channel activity by favoring the desensitized state. However, the mutant receptor is incapable of triggering ERK1/2 phosphorylation in response to the α7-agonist. Thus, while tyrosine phosphorylation is absolutely required for α7-triggered ERK pathway, it negatively modulates α7 ionotropic activity. Overall, phosphorylation/dephosphorylation events fine-tune the integrated cell response mediated by α7 activation, thus having a broad impact on α7 cholinergic signaling.
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