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α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs) subtype is widely expressed in mesolimbic dopaminergic pathway and other regions, which plays a vital role in modulating the release of multiple neurotransmitters and drug reward mechanisms. It has become a potential therapeutic target for the treatment of various neuropsychiatric disorders and drug addiction. However, most ligands identified with high affinity and selectivity targeting α6/α3β2β3 subtype showed limited subtype discrimination against the closely related α3β2 subtype. Furthermore, the molecular mechanisms underlying ligands interact with α6/α3β2β3 nAChR remain absent. In this study, the related approaches of site-directed mutagenesis of receptor, in vitro transcription and electrophysiological assay were utilized to establish the drug screening models of wild-type α6/α3β2β3 nAChR and its α6/α3 subunit single-point mutants. The effects led by single amino acid substitution to the function of α6/α3β2β3 nAChR were also evaluated. The animal experimental protocol involved in this study has been approved by the Ethics Committee of Guangxi University (Approval No: GXU-2023-0249). As the results showed, the half maximal effective concentration (EC50) for ACh activating α6/α3β2β3 nAChR was 18.5 μmol·L-1. All 7 single-point mutations of α6/α3 subunit resulted in increase of the agonist sensitivity, while the EC50 of ACh towards mutants α6/α3[V112E]β2β3、α6/α3[T147S]β2β3、α6/α3[E152K]β2β3 nAChR decreased to the greatest extent (EC50s were 3.5, 4.4, and 2.0 μmol·L-1, respectively, which were 0.1-0.2-fold relative to that of the wild-type receptor). These results established models for the research of structure-function relationship of α6/α3β2β3 nAChRs and molecular mechanism of ligand-receptor specific binding, as well as provided theoretical foundation for the design and optimization of selective drug leads targeting α6/α3β2β3 nAChRs.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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