| First Author | Pandey S | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 22 | Pages | 4605-4621.e11 |
| PubMed ID | 34582793 | Mgi Jnum | J:316937 |
| Mgi Id | MGI:6831140 | Doi | 10.1016/j.molcel.2021.09.007 |
| Citation | Pandey S, et al. (2021) Intrinsic bias at non-canonical, beta-arrestin-coupled seven transmembrane receptors. Mol Cell 81(22):4605-4621.e11 |
| abstractText | G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7TMRs), typically interact with two distinct signal-transducers, i.e., G proteins and beta-arrestins (betaarrs). Interestingly, there are some non-canonical 7TMRs that lack G protein coupling but interact with betaarrs, although an understanding of their transducer coupling preference, downstream signaling, and structural mechanism remains elusive. Here, we characterize two such non-canonical 7TMRs, namely, the decoy D6 receptor (D6R) and the complement C5a receptor subtype 2 (C5aR2), in parallel with their canonical GPCR counterparts. We discover that D6R and C5aR2 efficiently couple to betaarrs, exhibit distinct engagement of GPCR kinases (GRKs), and activate non-canonical downstream signaling pathways. We also observe that betaarrs adopt distinct conformations for D6R and C5aR2, compared to their canonical GPCR counterparts, in response to common natural agonists. Our study establishes D6R and C5aR2 as betaarr-coupled 7TMRs and provides key insights into their regulation and signaling with direct implication for biased agonism. |
