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"Protecting neurons from death during oxidative and neuroexcitotoxic stress is key for preventing cognitive dysfunction. We uncovered a novel neuroprotective mechanism involving interaction between neurotrophic factor-α1 (NF-α1/carboxypeptidase E, CPE) and human 5-HTR1E, a G protein-coupled serotonin receptor with no previously known neurological function. Co-immunoprecipitation and pull-down assays confirmed interaction between NFα1/CPE and 5-HTR1E and 125I NF-α1/CPE-binding studies demonstrated saturable, high-affinity binding to 5-HTR1E in stably transfected HEK293 cells (Kd = 13.82 nM). Treatment of 5-HTR1E stable cells with NF-α1/CPE increased pERK 1/2 and pCREB levels which prevented a decrease in pro-survival protein, BCL2, during H2O2-induced oxidative stress. Cell survival assay in β-arrestin Knockout HEK293 cells showed that the NF-α1/CPE-5-HTR1E-mediated protection against oxidative stress was β-arrestin-dependent. Molecular dynamics studies revealed that NF-α1/CPE interacts with 5-HTR1E via 3 salt bridges, stabilized by several hydrogen bonds, independent of the serotonin pocket. Furthermore, after phosphorylating the C-terminal tail and intracellular loop 3 (ICL3) of NF-α1/CPE-5-HTR1E, it recruited β-arrestin1 by forming numerous salt bridges and hydrogen bonds to ICL2 and ICL3, leading to activation of β-arrestin1. Immunofluorescence studies showed 5-HTR1E and NF-α1/CPE are highly expressed and co-localized on cell surface of human hippocampal neurons. Importantly, knock-down of 5-HTR1E in human primary neurons diminished the NF-α1/CPE-mediated protection of these neurons against oxidative stress and glutamate neurotoxicity-induced cell death. Thus, NF-α1/CPE uniquely interacts with serotonin receptor 5-HTR1E to activate the β-arrestin/ERK/CREB/BCL2 pathway to mediate stress-induced neuroprotection." Read full article

GPCR Binders, Drugs, and more Cytotoxicity-related effects of imidazolium and chlorinated bispyridinium

and transmitted to the intracellular face of the receptor, leading to the binding and activation of cytosolic The cytotoxic drug Monomethyl auristatin E (MMAE) was used alone or conjugated to either the native CCL5

The TM region contains discrete pockets accessible from the extracellular and cytosolic side of the membrane Neutralization of the negatively charged extracellular pocket Ex1 destabilizes the cytosolic helical

termination, highlighting the importance of studying their role in the activation of GPCRs2. β-arrestins are cytosolic scope, the authors challenged the current model, wich suggest that β-arrestin translocates from the cytosol interactions under unstimulated and stimulated conditions: Unstimulated condition: Inactive β-arrestin in the cytosol β-arrestin molecules remain on the plasma membrane briefly before dissociating and returning to the cytosol

GRK2 was shown to be expressed in human neutrophils and analysis of subcellular fractions revealed a cytosolic

can be categorised into two main sub-pathways based on their subcellular localisation: nuclear and cytosolic pathway typically involves ERK translocating into the nucleus to regulate gene expression, while the cytosolic

co-receptors inhibits the degradation of the transcriptional coactivator β-catenin by recruiting the cytosolic

and reversibility of the GloSensor™ cAMP assay, and which GloSensor™ version is optimal for measuring cytosolic

between the receptor-Gs and receptor-Gi complexes evidenced that 5-HT4/6/7-Gs coupled receptors have a cytosolic