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

Morri, Maurizio; Sanchez-Romero, Inmaculada; Tichy, Alexandra-Madelaine; Kainrath, Stephanie; Gerrard, Elliot J.; Hirschfeld, Priscila; Schwarz, Jan; Janovjak, Harald L

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

Morri M, Sanchez-Romero I, Tichy A-M, Kainrath S, Gerrard EJ, Hirschfeld P, Schwarz J, Janovjak HL. 2018. Optical functionalization of human class A orphan G-protein-coupled receptors. Nature Communications. 9(1), 1950.

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DOI

10.1038/s41467-018-04342-1

Journal Article | Published | English

Scopus indexed

Author

Morri, Maurizio^ISTA; Sanchez Romero, Inma^ISTA; Tichy, Alexandra-Madelaine^ISTA; Kainrath, Stephanie^ISTA; Gerrard, Elliot J.; Hirschfeld, Priscila^ISTA; Schwarz, Jan^ISTA; Janovjak, Harald L^ISTA

Department

Janovjak Group
Guet Group
Sixt Group

Grant

Microbial Ion Channels for Synthetic Neurobiology
Molecular Drug Targets

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.

Publishing Year

2018

Date Published

2018-12-01

Journal Title

Nature Communications

Volume

Issue

Article Number

1950

ISSN

2041-1723

IST-REx-ID

5984

Cite this

Morri M, Sanchez-Romero I, Tichy A-M, et al. Optical functionalization of human class A orphan G-protein-coupled receptors. Nature Communications. 2018;9(1). doi:10.1038/s41467-018-04342-1

Morri, M., Sanchez-Romero, I., Tichy, A.-M., Kainrath, S., Gerrard, E. J., Hirschfeld, P., … Janovjak, H. L. (2018). Optical functionalization of human class A orphan G-protein-coupled receptors. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-018-04342-1

Morri, Maurizio, Inmaculada Sanchez-Romero, Alexandra-Madelaine Tichy, Stephanie Kainrath, Elliot J. Gerrard, Priscila Hirschfeld, Jan Schwarz, and Harald L Janovjak. “Optical Functionalization of Human Class A Orphan G-Protein-Coupled Receptors.” Nature Communications. Springer Nature, 2018. https://doi.org/10.1038/s41467-018-04342-1.

M. Morri et al., “Optical functionalization of human class A orphan G-protein-coupled receptors,” Nature Communications, vol. 9, no. 1. Springer Nature, 2018.

Morri, Maurizio, et al. “Optical Functionalization of Human Class A Orphan G-Protein-Coupled Receptors.” Nature Communications, vol. 9, no. 1, 1950, Springer Nature, 2018, doi:10.1038/s41467-018-04342-1.

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