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Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses

Author

Listed:
  • 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))

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.

Suggested Citation

  • Rouven Schulz & Medina Korkut-Demirbaş & Alessandro Venturino & Gloria Colombo & Sandra Siegert, 2022. "Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses," Nature Communications, Nature, vol. 13(1), pages 1-26, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32390-1
    DOI: 10.1038/s41467-022-32390-1
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