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Chimeric human opsins as optogenetic light sensitisers
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Nuffield Laboratory of Ophthalmology, University of Oxford, UK; 4 School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Melbourne, Australia.ORCID iD: 0000-0003-0232-1812
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2021 (English)In: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 224, no 14, article id jeb240580Article in journal (Refereed) Published
Abstract [en]

Human opsin-based photopigments have great potential as light-sensitisers, but their requirement for phototransduction cascade-specific second messenger proteins may restrict their functionality in non-native cell types. In this study, eight chimeric human opsins were generated consisting of a backbone of either a rhodopsin (RHO) or long-wavelength-sensitive (LWS) opsin and intracellular domains from G(q/11)-coupled human melanopsin. Rhodopsin/melanopsin chimeric opsins coupled to both Gi and G(q/11) pathways. Greater substitution of the intracellular surface with corresponding melanopsin domains generally showed greater G(q/11) activity with a decrease in Gi activation. Unlike melanopsin, rhodopsin and rhodopsin/melanopsin chimeras were dependent upon exogenous chromophore to function. By contrast, wild-type LWS opsin and LWS opsin/melanopsin chimeras showed only weak Gi activation in response to light, whilst G(q/11) pathway activation was not detected. Immunocytochemistry (ICC) demonstrated that chimeric opsins with more intracellular domains of melanopsin were less likely to be trafficked to the plasma membrane. This study demonstrates the importance of Ga coupling efficiency to the speed of cellular responses and created human opsins with a unique combination of properties to expand the range of customised optogenetic biotools for basic research and translational therapies.

Place, publisher, year, edition, pages
Cambridge: Company of Biologists LTD , 2021. Vol. 224, no 14, article id jeb240580
Keywords [en]
Retina, Opsin, Chimera, G protein, Optogenetics, Phototransduction
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-187339DOI: 10.1242/jeb.240580ISI: 000681398200006PubMedID: 34151984Scopus ID: 2-s2.0-85111561747OAI: oai:DiVA.org:umu-187339DiVA, id: diva2:1593691
Available from: 2021-09-13 Created: 2021-09-13 Last updated: 2023-03-24Bibliographically approved

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Davies, Wayne I. L.

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