Department of Pharmacology and Therapeutics, University of Florida, P.O. Box 100267, Gainesville, FL, 32610-0267, USA.
Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Neuropharmacology. 2020 May 15;168:108021. doi: 10.1016/j.neuropharm.2020.108021. Epub 2020 Feb 28.
Postsynaptic nAChRs in the peripheral nervous system are critical for neuromuscular and autonomic neurotransmission. Pre- and peri-synaptic nAChRs in the brain modulate neurotransmission and are responsible for the addictive effects of nicotine. Subtypes of nAChRs in lymphocytes and non-synaptic locations may modulate inflammation and other cellular functions. All AChRs that function as ligand-gated ion channels are formed from five homologous subunits organized to form a central cation channel whose opening is regulated by ACh bound at extracellular subunit interfaces. nAChR subtype subunit composition can range from α7 homomers to α4β2α6β2β3 heteromers. Subtypes differ in affinities for ACh and other agonists like nicotine and in efficiencies with which their channels are opened and desensitized. Subtypes also differ in affinities for antagonists and for positive and negative allosteric modulators. Some agonists are "silent" with respect to channel opening, and AChRs may be able to signal metabotropic pathways by releasing G-proteins independent of channel opening. Electrophysiological studies that can resolve single-channel openings and molecular genetic approaches have allowed characterization of the structures of ligand binding sites, the cation channel, and the linkages between them, as well as the organization of AChR subunits and their contributions to function. Crystallography and cryo-electron-microscopy are providing increasing insights into the structures and functions of AChRs. However, much remains to be learned about both AChR structure and function, the in vivo functional roles of some AChR subtypes, and the development of better pharmacological tools directed at AChRs to treat addiction, pain, inflammation, and other medically important issues. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
外周神经系统中的突触后烟碱型乙酰胆碱受体（nAChRs）对于神经肌肉和自主神经递质传递至关重要。大脑中的前突触和突触周围 nAChRs 调节神经递质传递，并负责尼古丁的成瘾作用。淋巴细胞和非突触部位的 nAChRs 亚型可能调节炎症和其他细胞功能。所有作为配体门控离子通道发挥作用的 AChRs 都是由五个同源亚基组成的，这些亚基组织成一个中央阳离子通道，其开口由结合在细胞外亚基界面上的 ACh 调节。nAChR 亚型的亚基组成范围从α7 同源二聚体到α4β2α6β2β3 异源四聚体。亚型在对 ACh 和其他激动剂（如尼古丁）的亲和力以及通道开放和脱敏的效率方面存在差异。亚型在对拮抗剂和正、负变构调节剂的亲和力方面也存在差异。一些激动剂在通道开放方面是“沉默的”，AChRs 可以通过释放与通道开放无关的 G 蛋白来信号转导代谢型途径。能够解析单通道开放的电生理学研究和分子遗传学方法允许对配体结合位点、阳离子通道以及它们之间的连接以及 AChR 亚基的组织及其对功能的贡献进行表征。晶体学和冷冻电子显微镜学正在为了解 AChRs 的结构和功能提供越来越多的见解。然而，关于 AChR 的结构和功能、一些 AChR 亚型的体内功能作用以及开发针对 AChRs 的更好的药理学工具以治疗成瘾、疼痛、炎症和其他医学上重要的问题，仍有许多需要了解。本文是“当代尼古丁神经药理学进展”特刊的一部分。
