On January 2nd, Prof. Sun Jinpeng's team collaborated with Prof. Yi Fan’s team and Prof. Deng Cheng’s team to publish a research paper titled “Evolutionary Study and Structural Basis of Proton Sensing by Mus GPR4 and Xenopus GPR4” in Cell. The co-corresponding authors are Prof. Sun Jinpeng (School of Basic Medical Sciences, Institute of Advanced Medical Sciences, and NHC Key Laboratory of Otorhinolaryngology of Shandong University), Prof. Deng Cheng (West China Hospital of Sichuan University), Prof. Yang Fan, Prof. Zhang Pengju, and Prof.Yi Fan. Shandong University is credited as the first author and corresponding author institution.

In this study, the researchers observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7 cryo-EM structures of xtGPR4 and mmGPR4 under varying pH conditions, they identified that protonation of H^ECL2-45.47 and H^7.36 enabled polar network establishment and tighter association between the extracellular loop 2 (ECL2) and 7 transmembrane (7TM) domain, as well as a conserved propagating path, which are common mechanisms underlying protonation-induced GPR4 activation across different species. Moreover, protonation of distinct extracellular H^ECL2-45.41 contributed to the more acidic optimal pH range of xtGPR4. Overall, this study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.