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Genetically Targeted Optical Control of an Endogenous G Protein-Coupled Receptor

  • Prashant C. Donthamsetti
    Prashant C. Donthamsetti
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States
  • Johannes Broichhagen
    Johannes Broichhagen
    Department of Chemical Biology, Max Planck Institute for Medical Research, Jahnstraße 29, 69120 Heidelberg, Germany
  • Vojtech Vyklicky
    Vojtech Vyklicky
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States
  • Cherise Stanley
    Cherise Stanley
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States
  • Zhu Fu
    Zhu Fu
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States
    More by Zhu Fu
  • Meike Visel
    Meike Visel
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States
    More by Meike Visel
  • Joshua L. Levitz
    Joshua L. Levitz
    Department of Biochemistry, Weill Cornell Medical College, New York, New York 10024, United States
  • Jonathan A. Javitch
    Jonathan A. Javitch
    Departments of Psychiatry & Pharmacology, Columbia University, New York, New York 10032, United States
    Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, United States
  • Dirk Trauner
    Dirk Trauner
    Department of Chemistry, New York University, New York, New York 10003, United States
    More by Dirk Trauner
  • , and 
  • Ehud Y. Isacoff*
    Ehud Y. Isacoff
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States
    Helen Wills Neuroscience Institute, University of California, Berkeley, California, 94720, United States
    Molecular Biophysics & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
    *E-mail: [email protected]
Cite this: J. Am. Chem. Soc. 2019, 141, 29, 11522–11530
Publication Date (Web):June 24, 2019
https://doi.org/10.1021/jacs.9b02895
Copyright © 2019 American Chemical Society

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    Abstract

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    G protein-coupled receptors (GPCRs) are membrane proteins that play important roles in biology. However, our understanding of their function in complex living systems is limited because we lack tools that can target individual receptors with sufficient precision. State-of-the-art approaches, including DREADDs, optoXRs, and PORTL gated-receptors, control GPCR signaling with molecular, cell type, and temporal specificity. Nonetheless, these tools are based on engineered non-native proteins that may (i) express at nonphysiological levels, (ii) localize and turnover incorrectly, and/or (iii) fail to interact with endogenous partners. Alternatively, membrane-anchored ligands (t-toxins, DARTs) target endogenous receptors with molecular and cell type specificity but cannot be turned on and off. In this study, we used a combination of chemistry, biology, and light to control endogenous metabotropic glutamate receptor 2 (mGluR2), a Family C GPCR, in primary cortical neurons. mGluR2 was rapidly, reversibly, and selectively activated with photoswitchable glutamate tethered to a genetically targeted-plasma membrane anchor (membrane anchored Photoswitchable Orthogonal Remotely Tethered Ligand; maPORTL). Photoactivation was tuned by adjusting the length of the PORTL as well as the expression level and geometry of the membrane anchor. Our findings provide a template for controlling endogenous GPCRs with cell type specificity and high spatiotemporal precision.

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