ArticleMolecular pharmacology2013
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.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 38 citations in OpenAlex.
- Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder.Journal of autism and developmental disorders · 2014Trial
- Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia.Psychopharmacology · 2014Trial
- Reversal of repetitive TMS-induced LTP-like plasticity by a novel compound in rats.Frontiers in neural circuits · 2026Article
- The role of neuroactive steroids in psychiatric and neurological disorders: Neurobiology and therapeutic perspectives.Neuroscience and biobehavioral reviews · 2025Review
- Protein quality control ofFrontiers in cellular neuroscience · 2022Review
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis.Communications biology · 2021Article
- Positive and Negative Allosteric Modulators of N-Methyl-d-aspartate (NMDA) Receptors: Structure-Activity Relationships and Mechanisms of Action.Journal of medicinal chemistry · 2019Review
- Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders.Frontiers in endocrinology · 2019Review
- Differentially expressed genes in response to amitraz treatment suggests a proposed model of resistance to amitraz in R. decoloratus ticks.International journal for parasitology. Drugs and drug resistance · 2018Article
- Adrenocorticotropin Acutely Regulates Pregnenolone Sulfate Production by the Human Adrenal In Vivo and In Vitro.The Journal of clinical endocrinology and metabolism · 2018Article
- Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids.Current neuropharmacology · 2017Review
- Neuroplasticity pathways and protein-interaction networks are modulated by vortioxetine in rodents.BMC neuroscience · 2017Article
- Neuroactive Steroids: Receptor Interactions and Responses.Frontiers in neurology · 2017Review
- Sex Differences Distinguish Intracortical Glutamate Receptor-Mediated Regulation of Extracellular Dopamine Levels in the Prefrontal Cortex of Adult Rats.Cerebral cortex (New York, N.Y. : 1991) · 2016Article
- Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway.Translational psychiatry · 2015Article
- PKCε and allopregnanolone: functional cross-talk at the GABAA receptor level.Frontiers in cellular neuroscience · 2015Article
- A role for picomolar concentrations of pregnenolone sulfate in synaptic activity-dependent Ca2+ signaling and CREB activation.Molecular pharmacology · 2014Article
- Pregnenolone sulfate as a modulator of synaptic plasticity.Psychopharmacology · 2014Review
- Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies.Psychopharmacology · 2014Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.