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Optical functionalization of human Class A orphan G-protein-coupled receptors

Author

Listed:
  • Maurizio Morri

    (Institute of Science and Technology Austria (IST Austria))

  • Inmaculada Sanchez-Romero

    (Institute of Science and Technology Austria (IST Austria))

  • Alexandra-Madelaine Tichy

    (Institute of Science and Technology Austria (IST Austria))

  • Stephanie Kainrath

    (Institute of Science and Technology Austria (IST Austria))

  • Elliot J. Gerrard

    (The University of Manchester)

  • Priscila P. Hirschfeld

    (Institute of Science and Technology Austria (IST Austria))

  • Jan Schwarz

    (Institute of Science and Technology Austria (IST Austria))

  • Harald Janovjak

    (Institute of Science and Technology Austria (IST Austria))

Abstract

G-protein-coupled receptors (GPCRs) form the largest receptor family, relay environmental stimuli to changes in cell behavior and represent prime drug targets. Many GPCRs are classified as orphan receptors because of the limited knowledge on their ligands and coupling to cellular signaling machineries. Here, we engineer a library of 63 chimeric receptors that contain the signaling domains of human orphan and understudied GPCRs functionally linked to the light-sensing domain of rhodopsin. Upon stimulation with visible light, we identify activation of canonical cell signaling pathways, including cAMP-, Ca2+-, MAPK/ERK-, and Rho-dependent pathways, downstream of the engineered receptors. For the human pseudogene GPR33, we resurrect a signaling function that supports its hypothesized role as a pathogen entry site. These results demonstrate that substituting unknown chemical activators with a light switch can reveal information about protein function and provide an optically controlled protein library for exploring the physiology and therapeutic potential of understudied GPCRs.

Suggested Citation

  • Maurizio Morri & Inmaculada Sanchez-Romero & Alexandra-Madelaine Tichy & Stephanie Kainrath & Elliot J. Gerrard & Priscila P. Hirschfeld & Jan Schwarz & Harald Janovjak, 2018. "Optical functionalization of human Class A orphan G-protein-coupled receptors," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04342-1
    DOI: 10.1038/s41467-018-04342-1
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    Cited by:

    1. 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.

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