Orthogonal Optical Control of a G Protein-Coupled Receptor with a SNAP-Tethered Photochromic Ligand

  • ACS Cent Sci. 2015 Oct 28;1(7):383-93. doi: 10.1021/acscentsci.5b00260.
Johannes Broichhagen  1 ,  Arunas Damijonaitis  1 ,  Joshua Levitz  2 ,  Kevin R Sokol  1 ,  Philipp Leippe  1 ,  David Konrad  1 ,  Ehud Y Isacoff  3 ,  Dirk Trauner  1
Affiliations
  • 1. Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München, Germany; Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany.
  • 2. Department of Molecular and Cell Biology, University of California , Berkeley, California 94720, United States.
  • 3. 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; Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
PMID: 27162996 DOI: 10.1021/acscentsci.5b00260
Abstract

The covalent attachment of synthetic photoswitches is a general approach to impart light sensitivity onto native receptors. It mimics the logic of natural photoreceptors and significantly expands the reach of optogenetics. Here we describe a novel photoswitch design-the photoswitchable orthogonal remotely tethered ligand (PORTL)-that combines the genetically encoded SNAP-tag with photochromic ligands connected to a benzylguanine via a long flexible linker. We use the method to convert the G protein-coupled receptor mGluR2, a metabotropic glutamate receptor, into a photoreceptor (SNAG-mGluR2) that provides efficient optical control over the neuronal functions of mGluR2: presynaptic inhibition and control of excitability. The PORTL approach enables multiplexed optical control of different native receptors using distinct bioconjugation methods. It should be broadly applicable since SNAP-tags have proven to be reliable, many SNAP-tagged receptors are already available, and photochromic ligands on a long leash are readily designed and synthesized.

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