Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 27, Pages 13680-13689Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1900430116
Keywords
photopharmacology; photoactivation; pharmacological selectivity; functional silencing; 2-photon pharmacology
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Funding
- European Union Research and Innovation Programme Horizon 2020 [Human Brain Project SGA2 Grant] [785907]
- European Research ERA-Net SynBio programme (Modulightor project)
- Agency for Management of University and Research Grants/Generalitat de Catalunya (CERCA Programme) [2017-SGR-1442]
- Fonds Europeen de Developpement Economique et Regional (FEDER) funds
- Ministry of Economy and Competitiveness (MINECO)/FEDER [CTQ2016-80066-R]
- Fundaluce foundation
- FI fellowship from the Agency for Management of University and Research Grants/Generalitat de Catalunya [2014FI_B2 00160]
- Institute for Bioengineering of Catalonia Severo Ochoa International PhD Programme fellowship from MINECO
- H2020-MSCA-IF Reintegration Grant
- NIH/National Institute of Neurological Disorders and Stroke [R01NS099254]
- NSF Biophotonics Grant [1604544]
- MINECO [SAF2016-7426]
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1604544] Funding Source: National Science Foundation
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The physiological activity of proteins is often studied with loss-of-function genetic approaches, but the corresponding phenotypes develop slowly and can be confounding. Photopharmacology allows direct, fast, and reversible control of endogenous protein activity, with spatiotemporal resolution set by the illumination method. Here, we combine a photoswitchable allosteric modulator (alloswitch) and 2-photon excitation using pulsed near-infrared lasers to reversibly silence metabotropic glutamate 5 (mGlu(5)) receptor activity in intact brain tissue. Endogenous receptors can be photoactivated in neurons and astrocytes with pharmacological selectivity and with an axial resolution between 5 and 10 mu m. Thus, 2-photon pharmacology using alloswitch allows investigating mGlu(5)-dependent processes in wild-type animals, including synaptic formation and plasticity, and signaling pathways from intracellular organelles.
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