LAUSR.org creates dashboard-style pages of related content for over 1.5 million academic articles. Sign Up to like articles & get recommendations!

Arrestin-dependent nuclear export of phosphodiesterase 4D promotes GPCR-induced nuclear cAMP signaling required for learning and memory

Photo by dnevozhai from unsplash

G protein–coupled receptors (GPCRs) promote the expression of immediate early genes required for learning and memory. Here, we showed that β2-adrenergic receptor (β2AR) stimulation induced the nuclear export of phosphodiesterase… Click to show full abstract

G protein–coupled receptors (GPCRs) promote the expression of immediate early genes required for learning and memory. Here, we showed that β2-adrenergic receptor (β2AR) stimulation induced the nuclear export of phosphodiesterase 4D5 (PDE4D5), an enzyme that degrades the second messenger cAMP, to enable memory consolidation. We demonstrated that the endocytosis of β2AR phosphorylated by GPCR kinases (GRKs) mediated arrestin3-dependent nuclear export of PDE4D5, which was critical for promoting nuclear cAMP signaling and gene expression in hippocampal neurons for memory consolidation. Inhibition of the arrestin3-PDE4D5 association prevented β2AR-induced nuclear cAMP signaling without affecting receptor endocytosis. Direct PDE4 inhibition rescued β2AR-induced nuclear cAMP signaling and ameliorated memory deficits in mice expressing a form of the β2AR that could not be phosphorylated by GRKs. These data reveal how β2AR phosphorylated by endosomal GRK promotes the nuclear export of PDE4D5, leading to nuclear cAMP signaling, changes in gene expression, and memory consolidation. This study also highlights the translocation of PDEs as a mechanism to promote cAMP signaling in specific subcellular locations downstream of GPCR activation. Description β2-adrenoceptor activation stimulates the nuclear export of PDE4D5 to promote learning and memory. A nuclear exit to remember The nuclear accumulation of the second messenger cAMP elicits changes in gene expression in hippocampal neurons that underlie learning and memory. Martinez et al. found that stimulation of the β2-adrenergic receptor induced the nuclear export of the cAMP-degrading phosphodiesterase PDE4D5 to support nuclear cAMP signaling and memory consolidation (see also the Focus by Gurevich and Gurevich). This effect required the GRK-mediated phosphorylation of the β2-adrenergic receptor, which led to receptor endocytosis and association with arrestin3, a scaffold protein that triggered the nuclear export of PDE4D5. Mice expressing a mutant receptor lacking the GRK phosphorylation sites had memory deficits, which were attenuated by a PDE4 inhibitor. Thus, the β2-adrenergic receptor promotes memory consolidation by enabling cAMP propagation into the nucleus. —WW

Keywords: camp; nuclear camp; nuclear export; memory; camp signaling

Journal Title: Science Signaling
Year Published: 2023

Link to full text (if available)


Share on Social Media:                               Sign Up to like & get
recommendations!

Related content

More Information              News              Social Media              Video              Recommended



                Click one of the above tabs to view related content.