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Molecular Pharmacology

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Research ArticleArticle

A Role for Picomolar Concentrations of Pregnenolone Sulfate in Synaptic Activity-Dependent Ca2+ Signaling and CREB Activation

Conor C. Smith, Stella C. Martin, Kavitha Sugunan, Shelley J. Russek, Terrell T. Gibbs and David H. Farb
Molecular Pharmacology October 2014, 86 (4) 390-398; DOI: https://doi.org/10.1124/mol.114.094128
Conor C. Smith
Laboratory of Molecular Neurobiology (C.C.S., S.C.M., K.S., T.T.G., D.H.F.), Department of Pharmacology & Experimental Therapeutics, Laboratory of Translational Epilepsy (S.J.R.), Boston University School of Medicine, Boston, Massachusetts
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Stella C. Martin
Laboratory of Molecular Neurobiology (C.C.S., S.C.M., K.S., T.T.G., D.H.F.), Department of Pharmacology & Experimental Therapeutics, Laboratory of Translational Epilepsy (S.J.R.), Boston University School of Medicine, Boston, Massachusetts
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Kavitha Sugunan
Laboratory of Molecular Neurobiology (C.C.S., S.C.M., K.S., T.T.G., D.H.F.), Department of Pharmacology & Experimental Therapeutics, Laboratory of Translational Epilepsy (S.J.R.), Boston University School of Medicine, Boston, Massachusetts
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Shelley J. Russek
Laboratory of Molecular Neurobiology (C.C.S., S.C.M., K.S., T.T.G., D.H.F.), Department of Pharmacology & Experimental Therapeutics, Laboratory of Translational Epilepsy (S.J.R.), Boston University School of Medicine, Boston, Massachusetts
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Terrell T. Gibbs
Laboratory of Molecular Neurobiology (C.C.S., S.C.M., K.S., T.T.G., D.H.F.), Department of Pharmacology & Experimental Therapeutics, Laboratory of Translational Epilepsy (S.J.R.), Boston University School of Medicine, Boston, Massachusetts
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David H. Farb
Laboratory of Molecular Neurobiology (C.C.S., S.C.M., K.S., T.T.G., D.H.F.), Department of Pharmacology & Experimental Therapeutics, Laboratory of Translational Epilepsy (S.J.R.), Boston University School of Medicine, Boston, Massachusetts
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Abstract

Fast excitatory synaptic transmission that is contingent upon N-methyl d-aspartate receptor (NMDAR) function contributes to core information flow in the central nervous system and to the plasticity of neural circuits that underlie cognition. Hypoactivity of excitatory NMDAR-mediated neurotransmission is hypothesized to underlie the pathophysiology of schizophrenia, including the associated cognitive deficits. The neurosteroid pregnenolone (PREG) and its metabolites pregnenolone sulfate (PregS) and allopregnanolone in serum are inversely associated with cognitive improvements after oral PREG therapy, raising the possibility that brain neurosteroid levels may be modulated therapeutically. PregS is derived from PREG, the precursor of all neurosteroids, via a single sulfation step and is present at low nanomolar concentrations in the central nervous system. PregS, but not PREG, augments long-term potentiation and cognitive performance in animal models of learning and memory. In this report, we communicate the first observation that PregS, but not PREG, is a potent (EC50 ∼2 pM) enhancer of intracellular Ca2+ that is contingent upon neuronal activity, NMDAR-mediated synaptic activity, and L-type Ca2+ channel activity. Low picomolar PregS similarly activates cAMP response element-binding protein (CREB) phosphorylation (within 10 minutes), an essential memory molecule, via an extracellular-signal-regulated kinase/mitogen-activated protein kinase signal transduction pathway. Taken together, the results are consistent with a novel biologic role for the neurosteroid PregS that acts at picomolar concentrations to intensify the intracellular response to glutamatergic signaling at synaptic but not extrasynaptic, NMDARs by differentially augmenting CREB activation. This provides a genomic signal transduction mechanism by which PregS could participate in memory consolidation of relevance to cognitive function.

Footnotes

    • Received June 4, 2014.
    • Accepted July 21, 2014.
  • This work was supported by the National Institutes of Health National Institute of Mental Health [Grant R01MH049469] (to D.H.F.) and the National Institute of General Medical Sciences [Grant T32GM008541] (to D.H.F.)

  • dx.doi.org/10.1124/mol.114.094128.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (4)
Molecular Pharmacology
Vol. 86, Issue 4
1 Oct 2014
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Research ArticleArticle

Picomolar Pregnenolone Sulfate Activates Synaptic Activity and CREB

Conor C. Smith, Stella C. Martin, Kavitha Sugunan, Shelley J. Russek, Terrell T. Gibbs and David H. Farb
Molecular Pharmacology October 1, 2014, 86 (4) 390-398; DOI: https://doi.org/10.1124/mol.114.094128

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Research ArticleArticle

Picomolar Pregnenolone Sulfate Activates Synaptic Activity and CREB

Conor C. Smith, Stella C. Martin, Kavitha Sugunan, Shelley J. Russek, Terrell T. Gibbs and David H. Farb
Molecular Pharmacology October 1, 2014, 86 (4) 390-398; DOI: https://doi.org/10.1124/mol.114.094128
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