Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches

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• dc.contributor.author Izquierdo Serra, Mercè
• dc.contributor.author Bautista-Barrufet, Antoni
• dc.contributor.author Trapero, Ana
• dc.contributor.author Garrido-Charles, Aida
• dc.contributor.author Díaz-Tahoces, Ariadna
• dc.contributor.author Camarero, Nuria
• dc.contributor.author Pittolo, Silvia
• dc.contributor.author Valbuena, Sergio
• dc.contributor.author Pérez-Jiménez, Ariadna
• dc.contributor.author Gay, Marina
• dc.contributor.author García-Moll, Alejandro
• dc.contributor.author Llebaria, Amadeu
• dc.contributor.author Gorostiza, Pau
• dc.date.accessioned 2024-01-29T07:20:40Z
• dc.date.available 2024-01-29T07:20:40Z
• dc.date.issued 2016
• dc.description.abstract Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors and methods for covalent attachment depend on genetic manipulation. Here we introduce a chemical strategy to covalently conjugate and photoswitch the activity of endogenous proteins and demonstrate its application to the kainate receptor channel GluK1. The approach is based on photoswitchable ligands containing a short-lived, highly reactive anchoring group that is targeted at the protein of interest by ligand affinity. These targeted covalent photoswitches (TCPs) constitute a new class of light-regulated drugs and act as prosthetic molecules that photocontrol the activity of GluK1-expressing neurons, and restore photoresponses in degenerated retina. The modularity of TCPs enables the application to different ligands and opens the way to new therapeutic opportunities.
• dc.description.sponsorship We are grateful to G. Swanson (Northwestern University Feinberg School of Medicine) for the GluK1-2b receptor clone and advice for DRG neuronal culture, and to M. Mayer (National Institutes of Health) for GluK1 S1S2 plasmid and purification protocol. We also thank E. Vázquez (Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona) for providing the Origami-B (DE3) strain, and O. Seria, J.A. del Río, G. Callejo and X. Gasull for help with DRG neuron cultures. We are grateful to D. Soto and A. Llobet for helpful discussions. MS was performed at the IRB Barcelona Mass Spectrometry Core Facility, which actively participates in the BMBS European COST Action BM 1403 and is a member of Proteored, PRB2-ISCIII, supported by grant PRB2 (IPT13/0001-ISCIII-SGEFI / FEDER). We want to thank M. Vilaseca and M. Vilanova for technical support with MS. We acknowledge financial support from the RecerCaixa foundation (2010ACUP00378); the Marató de TV3 Foundation (grants 110231 and 111531); the Human Brain Project (HBP SGA 1), the Catalan government (2012FI_B 01122, 2014SGR-1251, 2014SGR-00109 and 2009SGR-1072); the Spanish Government (SAF2012-36375, CTQ2013-43892R and CTQ2014-57020-R); the Ramón Areces foundation and the ERANET Neuron LIGHTPAIN and SynBio MODULIGHTOR projects.
• dc.format.mimetype application/pdf
• dc.identifier.citation Izquierdo-Serra M, Bautista-Barrufet A, Trapero A, Garrido-Charles A, Díaz-Tahoces A, Camarero N, et al. Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches. Nat Commun. 2016 Jul 20;7(1):12221. DOI: 10.1038/ncomms12221
• dc.identifier.doi http://dx.doi.org/10.1038/ncomms12221
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/58845
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nature Communications. 2016 Jul 20;7(1):12221
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2012-36375
• dc.rights This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Medicaments
• dc.subject.other Medicaments biològics
• dc.subject.other Neurones
• dc.subject.other Visió
• dc.title Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion