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Molecular Pharmacology

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Research ArticleArticle

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

Emmanuel Kostakis, Conor Smith, Ming-Kuei Jang, Stella C. Martin, Kyle G. Richards, Shelley J. Russek, Terrell T. Gibbs and David H. Farb
Molecular Pharmacology August 2013, 84 (2) 261-274; DOI: https://doi.org/10.1124/mol.113.085696
Emmanuel Kostakis
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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Conor Smith
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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Ming-Kuei Jang
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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Stella C. Martin
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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Kyle G. Richards
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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Shelley J. Russek
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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Terrell T. Gibbs
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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David H. Farb
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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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 Ca2+-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.

Footnotes

    • Received February 18, 2013.
    • Accepted May 28, 2013.
  • E.K. and C.S. contributed equally to this work and are first coauthors.

  • T.T.G. and D.H.F. contributed equally to this work.

  • This work was supported in part by the National Institutes of Health National Institute of Mental Health [Grant R01MH049469]; and the National Institutes of Health National Institute of General Medical Sciences [Grant T32GM008541] (to D.H.F.).

  • dx.doi.org/10.1124/mol.113.085696.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (2)
Molecular Pharmacology
Vol. 84, Issue 2
1 Aug 2013
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Research ArticleArticle

Pregnenolone Sulfate Increases Active Surface NMDARs

Emmanuel Kostakis, Conor Smith, Ming-Kuei Jang, Stella C. Martin, Kyle G. Richards, Shelley J. Russek, Terrell T. Gibbs and David H. Farb
Molecular Pharmacology August 1, 2013, 84 (2) 261-274; DOI: https://doi.org/10.1124/mol.113.085696

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Research ArticleArticle

Pregnenolone Sulfate Increases Active Surface NMDARs

Emmanuel Kostakis, Conor Smith, Ming-Kuei Jang, Stella C. Martin, Kyle G. Richards, Shelley J. Russek, Terrell T. Gibbs and David H. Farb
Molecular Pharmacology August 1, 2013, 84 (2) 261-274; DOI: https://doi.org/10.1124/mol.113.085696
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