AIMMS researchers shine light on the signaling of G protein-coupled receptors

Niels Hauwert, Tamara Mocking and colleagues from the Division of Medicinal Chemistry have published an exciting technique in which a photoresponsive small molecule and light are used to dynamically modulate the signaling properties of a complex transmembrane protein, all with an unprecedented level of temporal resolution.

03/26/2018 | 4:35 PM

The research has been published in the prestigious Journal of the American Chemical Society.

Photopharmacology uses photons to control in situ the spatial and hence biological properties of photoswitchable small-molecule ligands and this technique is therefore complementary to the powerful approach of optogenetics, in which the protein itself is photoresponsive.

Histamine H3 receptor

Hauwert, Mocking and colleagues developed two azobenzene antagonists for an archetypical and complex GPCR (G protein-coupled receptor): the histamine H3 receptor (H3R). The two compounds, VUF14738 and VUF14862, swiftly and reversibly photoisomerize and show over 10-fold increased or decreased H3R binding affinities upon illumination at 360 nm. These complementary photoswitchable ligands successfully demonstrate repeated second-scale cycles of H3R photomodulation in oocytes.



The developed toolbox allows modulation of the H3R receptor with very high level of temporal resolution and dynamics, and can serve as a blueprint for photomodulation of the therapeutically highly relevant class of GPCR proteins.

On the longer run, the results could contribute to a novel class of medicines that can be activated in the body with light at a particular location and time point. This very property can render drugs safer.