Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Pharmacol
2013 Aug 01;842:261-74. doi: 10.1124/mol.113.085696.
Show Gene links
Show Anatomy links
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.
Kostakis E
,
Smith C
,
Jang MK
,
Martin SC
,
Richards KG
,
Russek SJ
,
Gibbs TT
,
Farb DH
.
???displayArticle.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.
Benveniste,
Trapping of glutamate and glycine during open channel block of rat hippocampal neuron NMDA receptors by 9-aminoacridine.
1995, Pubmed
Benveniste,
Trapping of glutamate and glycine during open channel block of rat hippocampal neuron NMDA receptors by 9-aminoacridine.
1995,
Pubmed
Berezhnoy,
Pharmacological Properties of DOV 315,090, an ocinaplon metabolite.
2008,
Pubmed
,
Xenbase
Broutman,
Involvement of the secretory pathway for AMPA receptors in NMDA-induced potentiation in hippocampus.
2001,
Pubmed
Chen,
Regulation of NMDA receptors by phosphorylation.
2007,
Pubmed
Chen,
PREGS induces LTP in the hippocampal dentate gyrus of adult rats via the tyrosine phosphorylation of NR2B coupled to ERK/CREB [corrected] signaling.
2007,
Pubmed
Chen,
Subtype-dependence of NMDA receptor channel open probability.
1999,
Pubmed
Dascal,
Role of calcium mobilization in mediation of acetylcholine-evoked chloride currents in Xenopus laevis oocytes.
1985,
Pubmed
,
Xenbase
Farb,
Uptake and release of [3H]gamma-aminobutyric acid by embryonic spinal cord neurons in dissociated cell culture.
1979,
Pubmed
Gaspar,
Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications.
2009,
Pubmed
Gibbs,
Sulfated steroids as endogenous neuromodulators.
2006,
Pubmed
Grosshans,
LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1.
2002,
Pubmed
Horak,
Subtype-dependence of N-methyl-D-aspartate receptor modulation by pregnenolone sulfate.
2006,
Pubmed
Jaconi,
Calcium release and influx colocalize to the endoplasmic reticulum.
1997,
Pubmed
,
Xenbase
Jang,
A steroid modulatory domain on NR2B controls N-methyl-D-aspartate receptor proton sensitivity.
2004,
Pubmed
,
Xenbase
Kaplan,
Biochemistry of Na,K-ATPase.
2002,
Pubmed
Klausner,
Brefeldin A: insights into the control of membrane traffic and organelle structure.
1992,
Pubmed
Kobayashi,
Functional ATPase activity of p97/valosin-containing protein (VCP) is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells.
2002,
Pubmed
Kostakis,
A steroid modulatory domain in NR2A collaborates with NR1 exon-5 to control NMDAR modulation by pregnenolone sulfate and protons.
2011,
Pubmed
,
Xenbase
Kwon,
Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses.
2008,
Pubmed
Labrie,
The involvement of the NMDA receptor D-serine/glycine site in the pathophysiology and treatment of schizophrenia.
2010,
Pubmed
Lan,
Protein kinase C modulates NMDA receptor trafficking and gating.
2001,
Pubmed
,
Xenbase
Lan,
Activation of metabotropic glutamate receptor 1 accelerates NMDA receptor trafficking.
2001,
Pubmed
,
Xenbase
Lau,
NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders.
2007,
Pubmed
Lau,
Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity.
2009,
Pubmed
Liere,
Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain.
2004,
Pubmed
Litchfield,
Protein kinase CK2: structure, regulation and role in cellular decisions of life and death.
2003,
Pubmed
Majewska,
Pregnenolone-sulfate: an endogenous antagonist of the gamma-aminobutyric acid receptor complex in brain?
1987,
Pubmed
Malayev,
Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids.
2002,
Pubmed
,
Xenbase
Mameli,
Alcohol increases efficacy of immature synapses in a neurosteroid-dependent manner.
2006,
Pubmed
Martin,
Molecular identification of the human GABABR2: cell surface expression and coupling to adenylyl cyclase in the absence of GABABR1.
1999,
Pubmed
Martina,
D1 and D4 dopaminergic receptor interplay mediates coincident G protein-independent and dependent regulation of glutamate NMDA receptors in the lateral amygdala.
2008,
Pubmed
Marx,
Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia.
2009,
Pubmed
Marx,
Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence.
2011,
Pubmed
McLean,
A minimal promoter for the GABA(A) receptor alpha6-subunit gene controls tissue specificity.
2000,
Pubmed
Milev,
Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up.
2005,
Pubmed
Misumi,
Novel blockade by brefeldin A of intracellular transport of secretory proteins in cultured rat hepatocytes.
1986,
Pubmed
Mizuta,
Gi-coupled γ-aminobutyric acid-B receptors cross-regulate phospholipase C and calcium in airway smooth muscle.
2011,
Pubmed
Nai,
Uncoupling the D1-N-methyl-D-aspartate (NMDA) receptor complex promotes NMDA-dependent long-term potentiation and working memory.
2010,
Pubmed
Nishizaki,
Store Ca2+ depletion enhances NMDA responses in cultured human astrocytes.
1999,
Pubmed
Noh,
Different signaling pathway between sphingosine-1-phosphate and lysophosphatidic acid in Xenopus oocytes: functional coupling of the sphingosine-1-phosphate receptor to PLC-xbeta in Xenopus oocytes.
1998,
Pubmed
,
Xenbase
Nong,
NMDA receptors are movin' in.
2004,
Pubmed
Oda,
Brefeldin A arrests the intracellular transport of a precursor of complement C3 before its conversion site in rat hepatocytes.
1987,
Pubmed
Park-Chung,
Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids.
1997,
Pubmed
,
Xenbase
Pei,
Regulation of dopamine D1 receptor function by physical interaction with the NMDA receptors.
2004,
Pubmed
Pellizzari,
Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses.
1999,
Pubmed
Rodríguez-Moreno,
Metabotropic actions of kainate receptors in the CNS.
2007,
Pubmed
Rozas,
Noncanonical signaling by ionotropic kainate receptors.
2003,
Pubmed
Sabeti,
Steroid pregnenolone sulfate enhances NMDA-receptor-independent long-term potentiation at hippocampal CA1 synapses: role for L-type calcium channels and sigma-receptors.
2007,
Pubmed
Sadri-Vakili,
Nanomolar concentrations of pregnenolone sulfate enhance striatal dopamine overflow in vivo.
2008,
Pubmed
Schumacher,
Pregnenolone sulfate in the brain: a controversial neurosteroid.
2008,
Pubmed
Skeberdis,
Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis.
2001,
Pubmed
,
Xenbase
Skeberdis,
mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C.
2001,
Pubmed
,
Xenbase
Sliwinski,
Pregnenolone sulfate enhances long-term potentiation in CA1 in rat hippocampus slices through the modulation of N-methyl-D-aspartate receptors.
2004,
Pubmed
Smallridge,
U-73122, an aminosteroid phospholipase C antagonist, noncompetitively inhibits thyrotropin-releasing hormone effects in GH3 rat pituitary cells.
1992,
Pubmed
Smith,
Receptor-coupled signal transduction in human polymorphonuclear neutrophils: effects of a novel inhibitor of phospholipase C-dependent processes on cell responsiveness.
1990,
Pubmed
Thompson,
The aminosteroid U-73122 inhibits muscarinic receptor sequestration and phosphoinositide hydrolysis in SK-N-SH neuroblastoma cells. A role for Gp in receptor compartmentation.
1991,
Pubmed
Ueda,
Neurosteroids stimulate G protein-coupled sigma receptors in mouse brain synaptic membrane.
2001,
Pubmed
Wang,
AMPA receptor-mediated regulation of a Gi-protein in cortical neurons.
1997,
Pubmed
Whittaker,
Pregnenolone sulfate induces NMDA receptor dependent release of dopamine from synaptic terminals in the striatum.
2008,
Pubmed
Wu,
Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.
1991,
Pubmed
Yao,
Quantal puffs of intracellular Ca2+ evoked by inositol trisphosphate in Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Zhang,
Na,K-ATPase activity regulates AMPA receptor turnover through proteasome-mediated proteolysis.
2009,
Pubmed
Zhang,
Isolation and characterization of the principal ATPase associated with transitional endoplasmic reticulum of rat liver.
1994,
Pubmed
Zheng,
Neuroactive steroid regulation of neurotransmitter release in the CNS: action, mechanism and possible significance.
2009,
Pubmed
Zheng,
Ca2+ influx amplifies protein kinase C potentiation of recombinant NMDA receptors.
1997,
Pubmed
,
Xenbase
