Kang et al. uncovered an intriguing new mechanism whereby G protein-coupled receptors (GPCRs) may signal to the nucleus to regulate gene transcription. The β-arrestins (βarrs), cytosolic proteins that are recruited to the plasma membrane to terminate GPCR signaling by promoting receptor desensitization and endocytosis, also act as scaffolding proteins in various cell signaling pathways (see Beaulieu and Caron). Kang et al. found that stimulation of the δ-opioid GPCR (DOR) in HEK293 cells transfected with DOR promoted nuclear accumulation of fluorescently labeled or HA-tagged βarr1. After microarray analysis revealed that βarr1 knockdown inhibited expression of p27 (which encodes a cyclin-dependent kinase inhibitor) and the transcription factor c-fos, the authors combined siRNA knockdown, βarr1 expression in mouse embryo fibroblasts or overexpression in HeLa cells, and pharmacological analysis to show that DOR stimulation acted through βarr1 to increase the abundance of p27 mRNA and protein. A mutant form of βarr1 that did not accumulate in the nucleus lacked these effects. Nuclear βarr1 participated in a complex with the transcription factor CREB (cAMP response element-binding protein) and recruited the histone acetyltransferase p300 to the promoter regions of c-fos and p27, enhancing the acetylation of histone H4. Similar effects on nuclear accumulation of βarr1, p27 transcription, and H4 acetylation at the p27 promoter were seen in human SK neuroblastoma cells that expressed endogenous DOR, and intracerebroventricular injection of a DOR agonist stimulated transcription of hippocampal p27 and H4 acetylation at the p27 promoter. Thus, the authors propose that stimulation of the DOR promotes translocation of βarr1 to the nucleus, where it recruits p300 to the promoters of target genes, stimulating local histone H4 acetylation and thereby gene transcription.
J. Kang, Y. Shi, B. Xiang, B. Qu, W. Su, M. Zhu, M. Zhang, G. Bao, F. Wang, X. Zhang, R. Yang, F. Fan, X. Chen, G. Pei, L. Ma, A nuclear function of β-arrestin1 in GPCR signaling: Regulation of histone acetylation and gene transcription. Cell 123, 833-847 (2005). [PubMed]
J.-M. Beaulieu, M. G. Caron, β-arrestin goes nuclear. Cell 123, 755-757 (2005). [PubMed]