| Structural highlights
Function
GPR4_MOUSE Proton-sensing G-protein coupled receptor couples to multiple intracellular signaling pathways, including GNAS/cAMP, GNAQ/phospholipase C (PLC), and GNA12/GNA13/Rho pathways (PubMed:17145776). Acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the GNA12/GNA13/Rho GTPase signaling pathway (PubMed:32058960). In the brain may mediate central respiratory sensitivity to CO(2)/H(+) (PubMed:26068853).[1] [2] [3]
Publication Abstract from PubMed
Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7-cryoelectron microscopy (cryo-EM) structures of Xenopus tropicalis GPR4 (xtGPR4) and Mus musculus GPR4 (mmGPR4) under varying pH conditions, we 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, our study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.
Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4.,Wen X, Shang P, Chen H, Guo L, Rong N, Jiang X, Li X, Liu J, Yang G, Zhang J, Zhu K, Meng Q, He X, Wang Z, Liu Z, Cheng H, Zheng Y, Zhang B, Pang J, Liu Z, Xiao P, Chen Y, Liu L, Luo F, Yu X, Yi F, Zhang P, Yang F, Deng C, Sun JP Cell. 2025 Feb 6;188(3):653-670.e24. doi: 10.1016/j.cell.2024.12.001. Epub 2025 , Jan 2. PMID:39753131[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yang LV, Radu CG, Roy M, Lee S, McLaughlin J, Teitell MA, Iruela-Arispe ML, Witte ON. Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Mol Cell Biol. 2007 Feb;27(4):1334-47. PMID:17145776 doi:10.1128/MCB.01909-06
- ↑ Kumar NN, Velic A, Soliz J, Shi Y, Li K, Wang S, Weaver JL, Sen J, Abbott SB, Lazarenko RM, Ludwig MG, Perez-Reyes E, Mohebbi N, Bettoni C, Gassmann M, Suply T, Seuwen K, Guyenet PG, Wagner CA, Bayliss DA. PHYSIOLOGY. Regulation of breathing by CO₂ requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science. 2015 Jun 12;348(6240):1255-60. PMID:26068853 doi:10.1126/science.aaa0922
- ↑ Krewson EA, Sanderlin EJ, Marie MA, Akhtar SN, Velcicky J, Loetscher P, Yang LV. The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells. iScience. 2020 Feb 21;23(2):100848. PMID:32058960 doi:10.1016/j.isci.2020.100848
- ↑ Wen X, Shang P, Chen H, Guo L, Rong N, Jiang X, Li X, Liu J, Yang G, Zhang J, Zhu K, Meng Q, He X, Wang Z, Liu Z, Cheng H, Zheng Y, Zhang B, Pang J, Liu Z, Xiao P, Chen Y, Liu L, Luo F, Yu X, Yi F, Zhang P, Yang F, Deng C, Sun JP. Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4. Cell. 2025 Feb 6;188(3):653-670.e24. PMID:39753131 doi:10.1016/j.cell.2024.12.001
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