Journal
ACTA PHARMACOLOGICA SINICA
Volume 37, Issue 1, Pages 44-55Publisher
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2015.127
Keywords
P2X receptors; ATP; ligand-gated ion channel; channel gating; allosteric change; drug design
Funding
- National Excellent Young Scientist Foundation of China [31222018]
- National Program on Key Basic Research Project of China [2014CB910302]
- National Natural Science Foundation of China [31570832, 31400707, 31170787]
- 'Shanghai Jiao Tong University-SMC Mutual Funds'
- Shanghai Jiao Tong University School of Medicine 'Key Incubation Project'
- Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine [BXJ201405]
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P2X receptors, as ATP-gated non-selective trimeric ion channels, are permeable to Na+, K+ and Ca2+. Comparing with other ligand-gated ion channel families, P2X receptors are distinct in their unique gating properties and pathophysiological roles, and have attracted attention as promising drug targets for a variety of diseases, such as neuropathic pain, multiple sclerosis, rheumatoid arthritis and thrombus. Several small molecule inhibitors for distinct P2X subtypes have entered into clinical trials. However, many questions regarding the gating mechanism of P2X remain unsolved. The structural determinations of P2X receptors at the resting and ATP-bound open states revealed that P2X receptor gating is a cooperative allosteric process involving multiple domains, which marks the beginning of the post-structure era of P2X research at atomic level. Here, we review the current knowledge on the structure-function relationship of P2X receptors, depict the whole picture of allosteric changes during the channel gating, and summarize the active sites that may contribute to new strategies for developing novel allosteric drugs targeting P2X receptors.
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