Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the gamma-secretase catalytic subunit, can affect amyloid-beta (Abeta) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how gamma-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including beta(2)-adrenergic receptor (beta(2)-AR). Here we report that activation of beta(2)-AR enhanced gamma-secretase activity and thus Abeta production. This enhancement involved the association of beta(2)-AR with presenilin-1 and required agonist-induced endocytosis of beta(2)-AR and subsequent trafficking of gamma-secretase to late endosomes and lysosomes, where Abeta production was elevated. Similar effects were observed after activation of delta-opioid receptor. Furthermore, chronic treatment with beta(2)-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, beta(2)-AR activation can stimulate gamma-secretase activity and amyloid plaque formation, which suggests that abnormal activation of beta(2)-AR might contribute to Abeta accumulation in Alzheimer disease pathogenesis.
Chromatin modification is considered to be a fundamental mechanism of regulating gene expression to generate coordinated responses to environmental changes, however, whether it could be directly regulated by signals mediated by G protein-coupled receptors (GPCRs), the largest surface receptor family, is not known. Here, we show that stimulation of delta-opioid receptor, a member of the GPCR family, induces nuclear translocation of beta-arrestin 1 (betaarr1), which was previously known as a cytosolic regulator and scaffold of GPCR signaling. In response to receptor activation, betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300, resulting in enhanced local histone H4 acetylation and transcription of these genes. Our results reveal a novel function of betaarr1 as a cytoplasm-nucleus messenger in GPCR signaling and elucidate an epigenetic mechanism for direct GPCR signaling from cell membrane to the nucleus through signal-dependent histone modification.
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