Organized cannabinoid receptor distribution in neurons revealed by super-resolution fluorescence imaging

G-protein-coupled receptors (GPCRs) play important roles in cellular functions. However, their intracellular organization is largely unknown. Through investigation of the cannabinoid receptor 1 (CB 1 ), we discovered periodically repeating clusters of CB 1 hotspots within the axons of neurons. We observed these CB 1 hotspots interact with the membrane-associated periodic skeleton (MPS) forming a complex crucial in the regulation of CB 1 signaling. Furthermore, we found that CB 1 hotspot periodicity increased upon CB 1 agonist application, and these activated CB 1 displayed less dynamic movement compared to non-activated CB 1 . Our results suggest that CB 1 forms periodic hotspots organized by the MPS as a mechanism to increase signaling efficacy upon activation. Despite the importance of G-protein-coupled receptors in many cellular functions, their intracellular organisation is largely unknown. The authors identified periodically repeating clusters of cannabinoid receptor 1 hotspots within neuronal axons that are dynamically regulated by CB 1 agonists.