Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses

Rouven Schulz, Medina Korkut-Demirbaş, Alessandro Venturino, Gloria Colombo and Sandra Siegert ()
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Rouven Schulz: Institute of Science and Technology Austria (ISTA)
Medina Korkut-Demirbaş: Institute of Science and Technology Austria (ISTA)
Alessandro Venturino: Institute of Science and Technology Austria (ISTA)
Gloria Colombo: Institute of Science and Technology Austria (ISTA)
Sandra Siegert: Institute of Science and Technology Austria (ISTA)

Nature Communications, 2022, vol. 13, issue 1, 1-26

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32390-1

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