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Start Over Author "Conor C. Smith" Journal molecular pharmacology
2 results on '"Conor C. Smith"'

1. 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

Author

David H. Farb, Stella C. Martin, Terrell T. Gibbs, Emmanuel Kostakis, Ming-Kuei Jang, Kyle G. Richards, Shelley J. Russek, and Conor C. Smith

Subjects
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
Abstract

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.

Published
2013

2. The neuroactive steroid pregnenolone sulfate stimulates trafficking of functional N-methyl D-aspartate receptors to the cell surface via a noncanonical, G protein, and Ca2+-dependent mechanism.

Author

Kostakis E, Smith C, Jang MK, Martin SC, Richards KG, Russek SJ, Gibbs TT, and Farb DH

Subjects
Animals, Cells, Cultured, Exocytosis drug effects, N-Methylaspartate metabolism, Neurons drug effects, Neurons metabolism, Oocytes drug effects, Oocytes metabolism, Protein Kinase C metabolism, Protein Transport drug effects, Rats, Receptors, GABA-A metabolism, Receptors, sigma metabolism, Xenopus laevis metabolism, Calcium metabolism, GTP-Binding Proteins metabolism, Pregnenolone pharmacology, Receptors, N-Methyl-D-Aspartate metabolism
Abstract

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.

Published
2013
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