Nanobody-mediated optical control of GPCRs with a photoswitchable ligand
Ion channels, transporters and receptors are crucial signaling proteins in the brain whose dysfunction are often at the root of neurological disorders, such as dementia and anxiety. A particularly important class of receptors are the G protein-coupled receptors (GPCRs). These receptors sit in the cell membrane and are sensors for signals in extracellular environment, including for neurotransmitters such as glutamate. Even though GPCRs are understood to play important roles in physiological processes, and are validated drug targets for a wide range of disorders, their precise mechanisms of signaling are not well understood. In order to shine light on their function, Dr. Johannes Broichhagen from the Max Planck Institute of Medical research and Prof. Joshua Levitz from Weill Cornell Medicine in New York have collaborated to design a light-dependent system for precise receptor activation and deactivation.
"We introduce a novel and, to date, most remote way of applying photoswitchable drugs" says Helen Farrants, a PhD student in the Department of Chemical Biology led by Prof. Kai Johnsson in Heidelberg. She continues: "by attaching the photoswitchable drugs to antibody-like proteins, we can choose to which GPCR the drugs go. We then use light to produce robust and reversible activation of downstream signaling from this specific GPCR". Because of its flexibility, this system could also be used to target other receptor sub types and be used with different photoswitchable drugs, allowing precise manipulation of signaling proteins both for mechanistic biological studies and for application in a clinical context.
This expansion of photopharmacology recently got accepted in ACS Chemical Biology (doi: 10.1021/acschembio.8b00628), and is a novel tool setting the stage for targeting endogenous receptors in vivo.
Read more: https://pubs.acs.org/doi/10.1021/acschembio.8b00628 "SNAP-tagged nanobodies enable reversible optical control of a G protein-coupled receptor via a remotely tethered photoswitchable ligand"