GPCR Phospho-Barcodes and Biased Signaling.

G protein-coupled receptors (GPCRs), the largest family of membrane receptors in humans, primarily regulate diverse physiological and pathological processes through G protein- and arrestin-mediated signaling pathways, making them important drug targets. Notably, arrestins not only mediate GPCR desensitization and internalization but also regulate G protein-independent signal transduction. However, the mechanisms underlying arrestin-mediated biased signaling remain incompletely understood, posing significant challenges for developing targeted GPCR drugs with signaling bias. To address this knowledge gap, researchers have conducted systematic investigations and proposed innovative models, including the flute model, the polyproline sorting dock model, and the time order effects of GPCR phospho-barcodes to elucidate the dynamic processes driving biased signaling in arrestin activations. These key findings not only refine the theoretical framework of GPCR phosphorylation in biased signaling but also provide a solid foundation for developing biased drugs targeting the GPCR-arrestin pathway, offering new opportunities for precision therapeutics in diverse diseases.