美国加州大学Ryan E. Hibbs团队近期取得重要工作进展，他们的最新研究揭示了发育肌肉中乙酰胆碱受体的结构转换。相关研究成果2024年7月31日在线发表于《自然》杂志上。

据介绍，在发育过程中，起源于脑干和脊髓的运动神经元与骨骼肌纤维形成精细的突触。这些神经元释放乙酰胆碱（ACh），与肌肉细胞上的烟碱ACh受体（AChR）结合，引发收缩。两种类型的AChR存在于发育中的肌肉细胞中，它们的差异表达是神经肌肉突触成熟的标志。胎儿肌肉受体向成人肌肉受体转变的结构原理尚不清楚。

研究人员展示了从发育过渡期的牛骨骼肌中分离出的胎儿和成人肌肉烟碱AChR的高分辨率结构。这些结构是在ACh存在和不存在的情况下获得的，为理解胎儿与成人受体亚型如何针对突触发育而调整，以及高保真骨骼肌收缩所需的全信号或无信号提供了结构背景。研究人员发现，ACh亲和力差异是由结合位点访问驱动的，通道电导是由广泛的表面静电调节的，开放持续时间的变化是由亚基内相互作用和结构灵活性引起的。

总之，这些结构进一步揭示了先天性肌无力综合征的致病机制。

附：英文原文

Title: Structural switch in acetylcholine receptors in developing muscle

Author: Li, Huanhuan, Teng, Jinfeng, Hibbs, Ryan E.

Issue&Volume: 2024-07-31

Abstract: During development, motor neurons originating in the brainstem and spinal cord form elaborate synapses with skeletal muscle fibres1. These neurons release acetylcholine (ACh), which binds to nicotinic ACh receptors (AChRs) on the muscle, initiating contraction. Two types of AChR are present in developing muscle cells, and their differential expression serves as a hallmark of neuromuscular synapse maturation2,3,4. The structural principles underlying the switch from fetal to adult muscle receptors are unknown. Here, we present high-resolution structures of both fetal and adult muscle nicotinic AChRs, isolated from bovine skeletal muscle in developmental transition. These structures, obtained in the absence and presence of ACh, provide a structural context for understanding how fetal versus adult receptor isoforms are tuned for synapse development versus the all-or-none signalling required for high-fidelity skeletal muscle contraction. We find that ACh affinity differences are driven by binding site access, channel conductance is tuned by widespread surface electrostatics and open duration changes result from intrasubunit interactions and structural flexibility. The structures further reveal pathogenic mechanisms underlying congenital myasthenic syndromes.

DOI: 10.1038/s41586-024-07774-6

Source: https://www.nature.com/articles/s41586-024-07774-6