Journal
BMC BIOLOGY
Volume 15, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12915-017-0380-8
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Funding
- BBSRC [BB/K002252/1]
- ERC [268970]
- Human Frontiers Science Project [RGP0034/2014]
- European Research Council (ERC) [268970] Funding Source: European Research Council (ERC)
- Biotechnology and Biological Sciences Research Council [BB/K002252/1, BB/I007296/1] Funding Source: researchfish
- Medical Research Council [G0801731] Funding Source: researchfish
- BBSRC [BB/I007296/1, BB/K002252/1] Funding Source: UKRI
- MRC [G0801731] Funding Source: UKRI
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Background: Endogenous circadian oscillators distributed across the mammalian body are synchronised among themselves and with external time via a variety of signalling molecules, some of which interact with G-protein-coupled receptors (GPCRs). GPCRs can regulate cell physiology via pathways originating with heterotrimeric G-proteins or beta-arrestins. We applied an optogenetic approach to determine the contribution of these two signalling modes on circadian phase. Results: We employed a photopigment (JellyOp) that activates Gas signalling with better selectivity and higher sensitivity than available alternatives, and a point mutant of this pigment (F112A) biased towards beta-arrestin signalling. When expressed in fibroblasts, both native JellyOp and the F112A arrestin-biased mutant drove light-dependent phase resetting in the circadian clock. Shifts induced by the two opsins differed in their circadian phase dependence and the degree to which they were associated with clock gene induction. Conclusions: Our data imply separable G-protein and arrestin inputs to the mammalian circadian clock and establish a pair of optogenetic tools suitable for manipulating Gas- and beta-arrestin-biased signalling in live cells.
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