The muscarinic M4 acetylcholine receptor exacerbates symptoms of movement disorders.
The muscarinic M4 acetylcholine receptor exacerbates symptoms of movement disorders.
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DOI：
10.1042/bst20220525
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发表时间：
2023-04-26
影响因子：
3.9
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中科院分区：
文献类型：
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Barbeau的多巴胺-乙酰胆碱平衡的跷跷板假说多年来一直主导着运动障碍文献。这两个简单的解释和运动障碍的抗胆碱能治疗的匹配疗效似乎支持这一假设。然而，来自运动障碍的转化和临床研究的证据表明，这种简单平衡的许多特征在运动障碍模型或这些疾病患者的成像研究中丢失、破坏或缺失。本文根据最近的证据重新评价多巴胺-乙酰胆碱平衡假说，并描述了Gαi/o偶联的毒蕈碱M4受体如何在基底神经节中与多巴胺信号传导相反地起作用。我们强调了M4信号如何改善或加剧运动障碍症状以及这些症状在特定疾病状态下的生理相关性。此外，我们提出了未来的研究方向，以充分了解M4靶向治疗运动障碍的潜在疗效。总体而言，初步证据表明，M4是一个有前途的药物靶点，以改善运动症状的低和高多巴胺能障碍。
Barbeau's seesaw hypothesis of dopamine-acetylcholine balance has predominated movement disorders literature for years. Both the simplicity of the explanation and the matching efficacy of anticholinergic treatment in movement disorders seem to support this hypothesis. However, evidence from translational and clinical studies in movement disorders indicates that many features of this simple balance are lost, broken, or absent from movement disorders models or in imaging studies of patients with these disorders. This review reappraises the dopamine-acetylcholine balance hypothesis in light of recent evidence and describes how the Gαi/o coupled muscarinic M4 receptor acts in opposition to dopamine signaling in the basal ganglia. We highlight how M4 signaling can ameliorate or exacerbate movement disorders symptoms and physiological correlates of these symptoms in specific disease states. Furthermore, we propose future directions for investigation of this mechanisms to fully understand the potential efficacy of M4 targeting therapeutics in movement disorders. Overall, initial evidence suggest that M4 is a promising pharmaceutical target to ameliorate motor symptoms of hypo- and hyper-dopaminergic disorders.