title: Orthogonal Optical Control of a G Protein-Coupled Receptor with a SNAP-Tethered Photochromic Ligand.
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.
authors.affiliation: 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.
authors.forename: Johannes
authors.initials: J
authors.lastname: Broichhagen
authors.affiliation: 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.
authors.forename: Arunas
authors.initials: A
authors.lastname: Damijonaitis
authors.affiliation: Department of Molecular and Cell Biology, University of California , Berkeley, California 94720, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Levitz
authors.affiliation: 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.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Sokol
authors.affiliation: 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.
authors.forename: Philipp
authors.initials: P
authors.lastname: Leippe
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Konrad
authors.affiliation: 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.
authors.forename: Ehud Y
authors.initials: EY
authors.lastname: Isacoff
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner