The Neuroactive Steroid Pregnenolone Sulfate Stimulates Trafficking of FunctionalN-Methyl D-Aspartate Receptors to the Cell Surface via a Noncanonical, G Protein, and Ca2+-Dependent Mechanism
| العنوان: | The Neuroactive Steroid Pregnenolone Sulfate Stimulates Trafficking of FunctionalN-Methyl D-Aspartate Receptors to the Cell Surface via a Noncanonical, G Protein, and Ca2+-Dependent Mechanism |
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| المؤلفون: | David H. Farb, Stella C. Martin, Terrell T. Gibbs, Emmanuel Kostakis, Ming-Kuei Jang, Kyle G. Richards, Shelley J. Russek, Conor C. Smith |
| المصدر: | Molecular Pharmacology. 84:261-274 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | medicine.medical_specialty, N-Methylaspartate, Neuroactive steroid, Allosteric regulation, Biology, Receptors, N-Methyl-D-Aspartate, Exocytosis, Xenopus laevis, chemistry.chemical_compound, GTP-Binding Proteins, Internal medicine, mental disorders, medicine, Animals, Receptors, sigma, Receptor, Cells, Cultured, Protein Kinase C, Neurons, Pharmacology, musculoskeletal, neural, and ocular physiology, Long-term potentiation, Articles, Receptors, GABA-A, Rats, Cell biology, Protein Transport, Endocrinology, nervous system, chemistry, Pregnenolone, Synaptic plasticity, Oocytes, Molecular Medicine, NMDA receptor, Calcium, Pregnenolone sulfate, medicine.drug |
| الوصف: | N-methyl D-aspartate (NMDA) receptors (NMDARs) mediate fast excitatory synaptic transmission and play a critical role in synaptic plasticity associated with learning and memory. NMDAR hypoactivity has been implicated in the pathophysiology of schizophrenia, and clinical studies have revealed reduced negative symptoms of schizophrenia with a dose of pregnenolone that elevates serum levels of the neuroactive steroid pregnenolone sulfate (PregS). This report describes a novel process of delayed-onset potentiation whereby PregS approximately doubles the cell's response to NMDA via a mechanism that is pharmacologically and kinetically distinct from rapid positive allosteric modulation by PregS. The number of functional cell-surface NMDARs in cortical neurons increases 60-100% within 10 minutes of exposure to PregS, as shown by surface biotinylation and affinity purification. Delayed-onset potentiation is reversible and selective for expressed receptors containing the NMDAR subunit subtype 2A (NR2A) or NR2B, but not the NR2C or NR2D, subunits. Moreover, substitution of NR2B J/K helices and M4 domain with the corresponding region of NR2D ablates rapid allosteric potentiation of the NMDA response by PregS but not delayed-onset potentiation. This demonstrates that the initial phase of rapid positive allosteric modulation is not a first step in NMDAR upregulation. Delayed-onset potentiation by PregS occurs via a noncanonical, pertussis toxin-sensitive, G protein-coupled, and Ca(2+)-dependent mechanism that is independent of NMDAR ion channel activation. Further investigation into the sequelae for PregS-stimulated trafficking of NMDARs to the neuronal cell surface may uncover a new target for the pharmacological treatment of disorders in which NMDAR hypofunction has been implicated. |
| تدمد: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.113.085696 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7fd9d78a5cc2939290654d76e0e6aef2 https://doi.org/10.1124/mol.113.085696 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7fd9d78a5cc2939290654d76e0e6aef2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210111 0026895X |
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| DOI: | 10.1124/mol.113.085696 |