A tale of two ATPs: biased activation of the P2X3 receptor

In a recent publication in Proceedings of the National Academy of Science, Wang et al. explore the structural and physiological outcomes of P2X3 receptor (P2X3R) activation by MgATP²⁻ and ATP⁴⁻, two endogenous forms of ATP. The authors find that the P2X3R, which mediates pain and taste perception as well as cough responses, exhibits distinct conformational changes in response to the two forms of ATP. Such behavior parallels the “biased agonism” observed in G protein-coupled receptors and may have important pharmacological implications. To demonstrate the potential utility of this finding, the authors show that two P2X3R inhibitors differentially block the two forms of ATP, with one reducing pain sensitivity and cough response without impacting sweet taste perception. These findings will help inform new therapeutic approaches to targeting the P2X3R, and potentially the broader P2X receptor family.