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.

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 Center for Integrated Protein Science Ludwig Maximilians University Munich Butenandtstraße 5 13 81377 Munich Germany

Department of Chemistry New York University 100 Washington Square East New York NY 10003 6699 USA Email

Department of Chemistry University of Milan Via Golgi 19 20133 Milan Italy

Dept of Physiology and Pharmacology Oregon Health and Science University Portland OR 97237 USA

European Molecular Biology Laboratory Cell Biology and Biophysics Unit Meyerhofstraße 1 69117 Heidelberg Germany Email

Institute of Metabolism and Systems Research University of Birmingham Birmingham B15 2TT UK Email

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo namesti 2 16610 Prague 6 Czech Republic

Max Planck Institute of Medical Research Jahnstr 29 69120 Heidelberg Germany

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