Optodynamic simulation of β-adrenergic receptor signalling

• Published in: Nature communications 2015-09, Vol.6 (1), p.8480-8480, Article 8480
• Main Authors: Siuda, Edward R., McCall, Jordan G., Al-Hasani, Ream, Shin, Gunchul, Il Park, Sung, Schmidt, Martin J., Anderson, Sonya L., Planer, William J., Rogers, John A., Bruchas, Michael R.
• Format: Article
• Language: English
• Subjects: 631/378; 631/45/612/194; 631/80/86; 64/110; 64/60; 692/308; 82/29; 96/10; 96/106; 96/109; 96/95; Animals; Anxiety - enzymology; beta-Adrenergic Receptor Kinases - metabolism; Cyclic AMP - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Male; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases - metabolism; multidisciplinary; Optogenetics; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9480

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/β 2 adrenergic receptor (opto-β 2 AR) is similar in dynamics to endogenous β 2 AR 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-β 2 AR 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 β 2 ARs. These new GPCR approaches enhance the utility of optogenetics and allow for discrete spatiotemporal control of GPCR signalling in vitro and in vivo . Optogenetic activation of β2-adrenergic receptors (β2-AR) has been achieved, but not characterized in detail. Here, Siuda et al . show that light-controlled opto-β2AR mimics endogenous β2AR activity in vitro and in vivo , and develop novel, optically active, functionally selective receptors to bias β2AR intracellular signaling mechanisms.