Fucile Sergio
Department of Physiology and Pharmacology "V. Erspamer", Sapienza Università di RomaRome, Italy.
Molecular Pathology, Istituto Neurologico Mediterraneo (IRCCS), Parco TecnologicoPozzilli, Italy.
Front Mol Neurosci. 2017 May 29;10:155. doi: 10.3389/fnmol.2017.00155. eCollection 2017.
Nicotinic acetylcholine receptors (nAChRs) are cation-selective ligand-gated ion channels exhibiting variable Ca permeability depending on their subunit composition. The Ca permeability is a crucial functional parameter to understand the physiological role of nAChRs, in particular considering their ability to modulate Ca-dependent processes such as neurotransmitter release. The rings of extracellular and intracellular charged amino acid residues adjacent to the pore-lining TM2 transmembrane segment have been shown to play a key role in the cation selectivity of these receptor channels, but to date a quantitative relationship between these structural determinants and the Ca permeability of nAChRs is lacking. In the last years the Ca permeability of several nAChR subtypes has been experimentally evaluated, in terms of fractional Ca current (, i.e., the percentage of the total current carried by Ca ions). In the present study, the available -values of nAChRs are used to build a simplified modular model describing the contribution of the charged residues in defined regions flanking TM2 to the selectivity filter controlling Ca influx. This model allows to predict the currently unknown -values of existing nAChRs, as well as the hypothetical Ca permeability of subunit combinations not able to assemble into functional receptors. In particular, basing on the amino acid sequences, a > 50% would be associated with homomeric nAChRs composed by different α subunits, excluding α7, α9, and α10. Furthermore, according to the model, human α7β2 receptors should have -values ranging from 3.6% (4:1 ratio) to 0.1% (1:4 ratio), much lower than the 11.4% of homomeric α7 nAChR. These results help to understand the evolution and the function of the large diversity of the nicotinic receptor family.
烟碱型乙酰胆碱受体（nAChRs）是阳离子选择性配体门控离子通道，根据其亚基组成表现出可变的钙通透性。钙通透性是理解nAChRs生理作用的关键功能参数，特别是考虑到它们调节钙依赖性过程（如神经递质释放）的能力。已证明与孔内衬TM2跨膜段相邻的细胞外和细胞内带电荷氨基酸残基环在这些受体通道的阳离子选择性中起关键作用，但迄今为止，这些结构决定因素与nAChRs钙通透性之间缺乏定量关系。在过去几年中，已通过分数钙电流（即钙离子携带的总电流的百分比）对几种nAChR亚型的钙通透性进行了实验评估。在本研究中，使用nAChRs的可用值构建一个简化的模块化模型，描述TM2侧翼特定区域中带电荷残基对控制钙内流的选择性过滤器的贡献。该模型能够预测现有nAChRs目前未知的值，以及无法组装成功能性受体的亚基组合的假设钙通透性。特别是，根据氨基酸序列，大于50%的钙通透性将与由不同α亚基组成的同聚体nAChRs相关，不包括α7、α9和α10。此外，根据该模型，人α7β2受体的钙通透性值应在3.6%（4:1比例）至0.1%（1:4比例）之间，远低于同聚体α7 nAChR的11.4%。这些结果有助于理解烟碱受体家族多样性的进化和功能。
