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Nat Commun. 2015 Sep 28;6:8480. doi: 10.1038/ncomms9480.

Optodynamic simulation of β-adrenergic receptor signalling.

Siuda ER1,2,3,4, McCall JG1,2,3,4, Al-Hasani R1,2,4, Shin G5, Il Park S5, Schmidt MJ1,2,4, Anderson SL1,2, Planer WJ1,2, Rogers JA5,6,7,8, Bruchas MR1,2,3,4,9.

Author information

1
Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St Louis, Missouri 63110, USA.
2
Washington University Pain Center, Washington University School of Medicine, St Louis, Missouri 63110, USA.
3
Division of Biology and Biomedical Sciences, Washington University School of Medicine, St Louis, Missouri 63110, USA.
4
Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
5
Department of Materials Science and Engineering, Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
6
Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
7
Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
8
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
9
Department of Biomedical Engineering, Washington University in St Louis, St Louis, Missouri 63110, USA.

Abstract

Optogenetics has provided a revolutionary approach to dissecting biological phenomena. However, the generation and use of optically active GPCRs in these contexts is limited and it is unclear how well an opsin-chimera GPCR might mimic endogenous receptor activity. Here we show that a chimeric rhodopsin/β2 adrenergic receptor (opto-β2AR) is similar in dynamics to endogenous β2AR in terms of: cAMP generation, MAP kinase activation and receptor internalization. In addition, we develop and characterize a novel toolset of optically active, functionally selective GPCRs that can bias intracellular signalling cascades towards either G-protein or arrestin-mediated cAMP and MAP kinase pathways. Finally, we show how photoactivation of opto-β2AR in vivo modulates neuronal activity and induces anxiety-like behavioural states in both fiber-tethered and wireless, freely moving animals when expressed in brain regions known to contain β2ARs. These new GPCR approaches enhance the utility of optogenetics and allow for discrete spatiotemporal control of GPCR signalling in vitro and in vivo.

PMID:
26412387
PMCID:
PMC4588095
DOI:
10.1038/ncomms9480
[Indexed for MEDLINE]
Free PMC Article

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