Optical control of GPR40 signalling in pancreatic β-cells

Abstract

Fatty acids activate GPR40 and K⁺ channels to modulate β-cell function. Herein, we describe the design and synthesis of <b>FAAzo-10</b>, a light-controllable GPR40 agonist based on Gw-9508. <b>FAAzo-10</b> is a potent GPR40 agonist in the <i>trans</i>-configuration and can be inactivated on isomerization to <i>cis</i> with UV-A light. Irradiation with blue light reverses this effect, allowing <b>FAAzo-10</b> activity to be cycled ON and OFF with a high degree of spatiotemporal precision. In dissociated primary mouse β-cells, <b>FAAzo-10</b> 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, <b>FAAzo-10</b> 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.