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.