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Ubiquitin-dependent lysosomal degradation of GPCRs and long-term desensitization GPCR ubiquitination, as shown initially for the β 2 AR and the chemokine receptor CXCR4, is a critical tag that directs internalized receptors to lysosomes, although initial agonist-induced endocytosis of these receptors does not require receptor ubiquitination [70, 77]