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Chem Sci. 2017 Nov 1;8(11):7604-7610. doi: 10.1039/c7sc01475a. Epub 2017 Aug 30.

Optical control of GPR40 signalling in pancreatic β-cells.

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Department of Chemistry , Center for Integrated Protein Science , Ludwig Maximilians University Munich , Butenandtstraße 5-13 , 81377 Munich , Germany.
European Molecular Biology Laboratory (EMBL) , Cell Biology & Biophysics Unit , Meyerhofstraße 1 , 69117 Heidelberg , Germany . Email:
Institute of Organic Chemistry and Biochemistry , Academy of Sciences of the Czech Republic , Flemingovo namesti 2 , 16610 Prague 6 , Czech Republic.
Institute of Metabolism and Systems Research (IMSR) , University of Birmingham , Birmingham , B15 2TT , UK . Email:
Centre for Endocrinology, Diabetes and Metabolism , Birmingham Health Partners , Birmingham , B15 2TH , UK.
COMPARE University of Birmingham and University of Nottingham Midlands , UK.
Department of Chemistry , University of Milan , Via Golgi 19 , 20133 , Milan , Italy.
Max-Planck Institute of Medical Research , Jahnstr. 29 , 69120 Heidelberg , Germany.
Dept. of Physiology and Pharmacology , Oregon Health and Science University , Portland , OR 97237 , USA.
Department of Chemistry , New York University , 100 Washington Square East , New York , NY 10003-6699 , USA . Email:


Fatty acids activate GPR40 and K+ channels to modulate β-cell function. Herein, we describe the design and synthesis of FAAzo-10, a light-controllable GPR40 agonist based on Gw-9508. FAAzo-10 is a potent GPR40 agonist in the trans-configuration and can be inactivated on isomerization to cis with UV-A light. Irradiation with blue light reverses this effect, allowing FAAzo-10 activity to be cycled ON and OFF with a high degree of spatiotemporal precision. In dissociated primary mouse β-cells, FAAzo-10 also inactivates voltage-activated and ATP-sensitive K+ channels, and allows us to control glucose-stimulated Ca2+ oscillations in whole islets with light. As such, FAAzo-10 is a useful tool to study the complex effects, with high specificity, which FA-derivatives such as Gw-9508 exert at multiple targets in mouse β-cells.

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