Finely ordered intracellular domain harbors an allosteric site to modulate physiopathological function of P2X3 receptors

Yi-Yu Lin, Yan Lu, Chun-Yun Li, Xue-Fei Ma, Miao-Qing Shao, Yu-Hao Gao, Yu-Qing Zhang, Hai-Ning Jiang, Yan Liu, Yang Yang, Li-Dong Huang, Peng Cao, Heng-Shan Wang (), Jin Wang () and Ye Yu ()
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Yi-Yu Lin: China Pharmaceutical University
Yan Lu: China Pharmaceutical University
Chun-Yun Li: China Pharmaceutical University
Xue-Fei Ma: China Pharmaceutical University
Miao-Qing Shao: China Pharmaceutical University
Yu-Hao Gao: China Pharmaceutical University
Yu-Qing Zhang: China Pharmaceutical University
Hai-Ning Jiang: Shanghai Jiao Tong University School of Medicine
Yan Liu: Shanghai Jiao Tong University School of Medicine
Yang Yang: Shanghai Jiao Tong University School of Medicine
Li-Dong Huang: Shanghai Jiao Tong University School of Medicine
Peng Cao: Nanjing University of Chinese Medicine
Heng-Shan Wang: School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University
Jin Wang: China Pharmaceutical University
Ye Yu: China Pharmaceutical University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract P2X receptors, a subfamily of ligand-gated ion channels activated by extracellular ATP, are implicated in various physiopathological processes, including inflammation, pain perception, and immune and respiratory regulations. Structural determinations using crystallography and cryo-EM have revealed that the extracellular three-dimensional architectures of different P2X subtypes across various species are remarkably identical, greatly advancing our understanding of P2X activation mechanisms. However, structural studies yield paradoxical architectures of the intracellular domain (ICD) of different subtypes (e.g., P2X3 and P2X7) at the apo state, and the role of the ICD in P2X functional regulation remains unclear. Here, we propose that the P2X3 receptor’s ICD has an apo state conformation similar to the open state but with a less tense architecture, containing allosteric sites that influence P2X3’s physiological and pathological roles. Using covalent occupancy, engineered disulfide bonds and voltage-clamp fluorometry, we suggested that the ICD can undergo coordinated motions with the transmembrane domain of P2X3, thereby facilitating channel activation. Additionally, we identified a novel P2X3 enhancer, PSFL77, and uncovered its potential allosteric site located in the 1α3β domain of the ICD. PSFL77 modulated pain perception in P2rx3+/+, but not in P2rx3−/−, mice, indicating that the 1α3β, a “tunable” region implicated in the regulation of P2X3 functions. Thus, when P2X3 is in its apo state, its ICD architecture is fairly ordered rather than an unstructured outward folding, enabling allosteric modulation of the signaling of P2X3 receptors.

Date: 2024
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DOI: 10.1038/s41467-024-51815-7

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