Optical control of GPR40 signalling in pancreatic beta-cells
Frank JA., Yushchenko DA., Fine NHF., Duca M., Citir M., Broichhagen J., Hodson DJ., Schultz C., Trauner D.
Fatty acids activate GPR40 and K(+) channels to modulate beta-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 beta-cells, FAAzo-10 also inactivates voltage-activated and ATP-sensitive K(+) channels, and allows us to control glucose-stimulated Ca(2+) 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 beta-cells.