Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses

article Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses published yes Rouven Schulz author 4C5E7B96-F248-11E8-B48F-1D18A9856A870000-0001-5297-733X Medina Korkut author 4B51CE74-F248-11E8-B48F-1D18A9856A870000-0003-4309-2251 Alessandro Venturino author 41CB84B2-F248-11E8-B48F-1D18A9856A870000-0003-2356-9403 Gloria Colombo author 3483CF6C-F248-11E8-B48F-1D18A9856A870000-0001-9434-8902 Sandra Siegert author 36ACD32E-F248-11E8-B48F-1D18A9856A870000-0001-8635-0877 SaSi department Modulating microglia through G protein-coupled receptor (GPCR) signaling project G protein-coupled receptors (GPCRs) regulate processes ranging from immune responses to neuronal signaling. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additionally, dissecting cell type-specific responses is challenging when the same GPCR is expressed on different cells within a tissue. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that bind clozapine-N-oxide and mimic a GPCR-of-interest. We show that chimeric DREADD-β2AR triggers responses comparable to β2AR on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Moreover, we successfully recapitulate β2AR-mediated filopodia formation in microglia, an immune cell capable of driving central nervous system inflammation. When dissecting microglial inflammation, we included two additional DREADD-based chimeras mimicking microglia-enriched GPR65 and GPR109A. DREADD-β2AR and DREADD-GPR65 modulate the inflammatory response with high similarity to endogenous β2AR, while DREADD-GPR109A shows no impact. Our DREADD-based approach allows investigation of cell type-dependent pathways without known endogenous ligands. https://research-explorer.ista.ac.at/download/11995/12002/2022_NatComm_Schulz.pdf application/pdfno Springer Nature2022 eng Nature Communications 2041-1723 35970889 00084098440003210.1038/s41467-022-32390-1 13 https://research-explorer.ista.ac.at/record/11542 https://research-explorer.ista.ac.at/record/11945 https://ista.ac.at/en/news/dreaddful-mimicry/ R. Schulz, M. Korkut, A. Venturino, G. Colombo, S. Siegert, Nature Communications 13 (2022). R. Schulz, M. Korkut, A. Venturino, G. Colombo, and S. Siegert, “Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses,” Nature Communications, vol. 13. Springer Nature, 2022. Schulz R, Korkut M, Venturino A, Colombo G, Siegert S. Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. Nature Communications. 2022;13. doi:<a href="https://doi.org/10.1038/s41467-022-32390-1">10.1038/s41467-022-32390-1</a> Schulz, R., Korkut, M., Venturino, A., Colombo, G., & Siegert, S. (2022). Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. Nature Communications. Springer Nature. <a href="https://doi.org/10.1038/s41467-022-32390-1">https://doi.org/10.1038/s41467-022-32390-1</a> Schulz R, Korkut M, Venturino A, Colombo G, Siegert S. 2022. Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. Nature Communications. 13, 4728. Schulz, Rouven, Medina Korkut, Alessandro Venturino, Gloria Colombo, and Sandra Siegert. “Chimeric GPCRs Mimic Distinct Signaling Pathways and Modulate Microglia Responses.” Nature Communications. Springer Nature, 2022. <a href="https://doi.org/10.1038/s41467-022-32390-1">https://doi.org/10.1038/s41467-022-32390-1</a>. Schulz, Rouven, et al. “Chimeric GPCRs Mimic Distinct Signaling Pathways and Modulate Microglia Responses.” Nature Communications, vol. 13, 4728, Springer Nature, 2022, doi:<a href="https://doi.org/10.1038/s41467-022-32390-1">10.1038/s41467-022-32390-1</a>. 119952022-08-28T22:01:59Z2026-04-07T14:17:58Z