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 CB1 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 CB1 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 when being activated.