His452Tyr polymorphism in the human 5-HT2A receptor affects clozapine-induced signaling networks revealed by quantitative phosphoproteomics
| العنوان: | His452Tyr polymorphism in the human 5-HT2A receptor affects clozapine-induced signaling networks revealed by quantitative phosphoproteomics |
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| المؤلفون: | José Brea, Marta Cimadevila, Alba Iglesias, David Martín-Oliva, M. Isabel Loza, Pedro R. Cutillas, Juan F. López-Giménez, Javier González-Maeso, Sandra M. Martín-Guerrero, Paula Alonso, Pedro Casado |
| المصدر: | Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) Digital.CSIC. Repositorio Institucional del CSIC instname |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Pharmacology, biology, Phosphoproteomics, Biochemistry, Cell biology, 03 medical and health sciences, Insulin receptor, 030104 developmental biology, 0302 clinical medicine, ErbB, 030220 oncology & carcinogenesis, 5-HT2A receptor G protein-coupled receptor (GPCR) Polymorphism Antipsychotics Clozapine Schizophrenia Phosphoproteomics, medicine, biology.protein, Phosphorylation, Protein phosphorylation, Signal transduction, Clozapine, medicine.drug, G protein-coupled receptor |
| الوصف: | Antipsychotic drugs remain the current standard for schizophrenia treatment. Although they directly recognize the orthosteric binding site of numerous monoaminergic G protein-coupled receptors (GPCRs), these drugs, and particularly second-generation antipsychotics such as clozapine, all have in common a very high affinity for the serotonin 5-HT2A receptor (5-HT2AR). Using classical pharmacology and targeted signaling pathway assays, previous findings suggest that clozapine and other atypical antipsychotics behave principally as 5-HT2AR neutral antagonists and/or inverse agonists. However, more recent findings showed that antipsychotics may also behave as pathway-specific agonists. Reversible phosphorylation is a common element in multiple signaling networks. Combining a quantitative phosphoproteomic method with signaling network analysis, we tested the effect of clozapine treatment on the overall level of protein phosphorylation and signal transduction cascades in vitro in mammalian cell lines induced to express either the human 5-HT2AR or the H452Y variant of the gene encoding the 5-HT2AR receptor. This naturally occurring variation within the 5-HT2AR gene was selected because it has been repeatedly associated with schizophrenia patients who do not respond to clozapine treatment. Our data show that short time exposure (5 or 10 min) to clozapine (10−5 M) led to phosphorylation of numerous signaling components of pathways involved in processes such as endocytosis, ErbB signaling, insulin signaling or estrogen signaling. Cells induced to express the H452Y variant showed a different basal phosphoproteome, with increases in the phosphorylation of mTOR signaling components as a translationally relevant example. However, the effect of clozapine on the functional landscape of the phosphoproteome was significantly reduced in cells expressing the 5-HT2AR-H452Y construct. Together, these findings suggest that clozapine behaves as an agonist inducing phosphorylation of numerous pathways downstream of the 5-HT2AR, and that the single nucleotide polymorphism encoding 5-HT2AR-H452Y affects these clozapine-induced phosphorylation-dependent signaling networks. |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ad5de8912403d5120941bb0a2b34e9dc http://hdl.handle.net/10261/248807 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ad5de8912403d5120941bb0a2b34e9dc |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |