Browsing by Author "Hassan, Ahmed Tarek Ahmed"

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    The role of Beta-arrestin2 nuclear signalling in neuroplasticity
    (2021-03) Hassan, Ahmed Tarek Ahmed; Altier, Christophe; Dufour, Antoine Hugues-Olivier; Hollenberg, Morley Donald
    Pain is a cardinal symptom of inflammation. The protein transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel that plays a key role in sensing and transducing inflammatory pain signals. Our lab has shown that activation of TRPV1 by its agonist capsaicin, induces the shuttling of β -arrestin2 (ARRB2) from the cytoplasm to the nucleus in HEK 293 cells and DRG neurons 1.. However, the functional role of ARRB2 in the nucleus has remained unknown. Here, we first assessed the effect of TRPV1 activation on ARRB2 conformation using an intramolecular fluorescent arsenical hairpin (FlAsH) bioluminescence resonance energy transfer (BRET) method, we demonstrated that TRPV1 activation, via calcium influx, induces conformational changes of ARRB2. Next, we investigated the ARRB2 nuclear interactome by conducting a global proteomic analysis of nuclear versus cytosolic ARRB2-interacting proteins in a heterologous expression system. We identified clusters of proteins that localize to the nucleolus that are involved in processes related to ribosomal biogenesis. Indeed, ARRB2 was shown to interact and co-localize with the proteins; the nucleolar marker nucleophosmin 1 (NPM1) and Treacle Ribosome Biogenesis Factor 1 (TCOF1). We further investigated the role of ARRB2 interactions with the ribosomal biogenesis machinery in regulating neuroplasticity. Using neuroblastoma (neuro2a) cells and dorsal root ganglia (DRG) neurons, we found that L395Q ARRB2 mutant increased POL I activity, inhibited the tumor suppressorp53 (p53) level and caused a decrease in the outgrowth of neurites. Our results suggest that TRPV1 can potentially regulates neuroplasticity through triggering a functional interaction of ARRB2 with proteins involved in ribosomal biogenesis.