| Structural highlights
Function
GRM8_HUMAN G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity.[1]
Publication Abstract from PubMed
Metabotropic glutamate receptors (mGluRs) are dimeric class C G protein-coupled receptors, which play crucial roles in brain physiology and pathology. Among them, mGlu8 is the least characterized, though it is physiologically important. While recognized to signal via G(i/o) proteins, the involvement of beta-arrestin is unknown. Here, we found that both mGlu8 agonists and positive allosteric modulators (PAMs) activate G(i) signaling, but mainly agonists induce beta-arrestin recruitment. We solved five human mGlu8 cryo-electron microscopy (cryo-EM) structures in various states: apo, antagonist-bound, agonist + PAM-bound, agonist + PAM-bound with G(i) protein, and agonist-bound with beta-arrestin1 states. They revealed a unique PAM-binding pocket at the extracellular side of the TM6/TM7 interface. Agonist and PAM promote active mGlu8 association with one G(i) protein asymmetrically (2:1), while two beta-arrestin1 can interact symmetrically (2:2) to both subunits of an inactive dimer state to promote constitutive internalization. These findings elucidate how mGlu8 selectively engages transducers, offering insights into its signaling capabilities and selective drug development.
Structural characterization of five functional states of metabotropic glutamate receptor 8.,Zhao J, Deng Y, Xu Z, Xu C, Zhao C, Li Z, Sun H, Tian X, Song Y, Cimadevila M, Wang H, Liu Y, Zhang X, Chen Y, Sun S, Yong X, Su L, He Y, Zhong Y, Yang H, Pin JP, Yan W, Shao Z, Liu J Mol Cell. 2025 Sep 18;85(18):3460-3473.e6. doi: 10.1016/j.molcel.2025.08.019. PMID:40972528[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR Jr, Johnson BG, Schoepp DD, Belagaje RM. Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells. Brain Res Mol Brain Res. 1998 Jan;53(1-2):88-97. PMID:9473604
- ↑ Zhao J, Deng Y, Xu Z, Xu C, Zhao C, Li Z, Sun H, Tian X, Song Y, Cimadevila M, Wang H, Liu Y, Zhang X, Chen Y, Sun S, Yong X, Su L, He Y, Zhong Y, Yang H, Pin JP, Yan W, Shao Z, Liu J. Structural characterization of five functional states of metabotropic glutamate receptor 8. Mol Cell. 2025 Sep 18;85(18):3460-3473.e6. PMID:40972528 doi:10.1016/j.molcel.2025.08.019
|
