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DeNies et al. identify a new mechanism of intracellular GPCR signalling. Using CXC chemokine receptor 4 (CXCR4) as a model, they show that upon stimulation with receptor agonists that not only plasma membrane-localized receptors, but also intracellular CXCR4 molecules are post-translationally modified and regulate transcription. This study suggests that a small pool of plasma membrane-localized GPCRs can activate internal receptor-dependent signaling, and that β-arrestin-1 mediates this activation.