NANOSENSORS REVEAL THE PROPERTIES OF NATIVE GPCRS IN NEURONS
G protein-coupled receptors are the first targets of drugs, and therefore the preferred targets of the pharmaceutical industry. Today, these receptors are mainly studied in cell lines where they are over-expressed. However, it is essential to be able to study their properties in their native environment, particularly in neurons with multiple sub-compartments such as synaptic terminals, dendrites or spines.
The team “Neuroreceptors, dynamics and function” headed by Philippe Rondard, in collaboration with Chanjuan Xu and Jianfeng Liu (University of Wuhan, China) who have optimized G protein nano-sensors using nanoluciferase, has detected the activity of various G proteins in transfected neurons, in microplate format, making pharmacological analyses very easy. Using highly sensitive Gi/o sensors, the properties of three GPCRs, the native GABAB, CB1 cannabinoid and alpha2a adrenergic receptors, were studied and compared in primary cultured neurons and in HEK293 cells over-expressing these receptors. The results show different pharmacological properties and activation profiles of various G proteins between transfected and native receptors. This demonstrates the importance of receptor environment in their signaling properties. Even if this was expected, given the interacting proteins and sub-compartment localizations, this study also illustrates the importance of using primary cell-compatible biosensors to assess the activities of endogenous GPCRs in their native environment.
This work was accepted for publication in Nature Communications.
The coupling efficiency profile of GABAB and CB1 receptors to different G proteins differs between recombinant receptors in HEK cells and native receptors in neurons.
