ArticleJournal of neurochemistry2011
A steroid modulatory domain in NR2A collaborates with NR1 exon-5 to control NMDAR modulation by pregnenolone sulfate and protons.
Article in Journal of neurochemistry, 2011. 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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Who cites it
23 citing papers in PubMed, 30 citations in OpenAlex.
- Stimulus-Transcription Coupling of TRPM3 Channels: A Signaling Pathway from the Plasma Membrane to the Nucleus.Biomolecules · 2025Review
- Ginkgo Biloba as a niche theme cognitive enhancer agent, 1420 dokumen of Scopus database. A bibliometric study from 1988 to 2024.F1000Research · 2025Article
- Rescuing tri-heteromeric NMDA receptor function: the potential of pregnenolone-sulfate in loss-of-function GRIN2B variants.Cellular and molecular life sciences : CMLS · 2024Article
- Novel neuroactive steroids as positive allosteric modulators of NMDA receptors: mechanism, site of action, and rescue pharmacology on GRIN variants associated with neurological conditions.Cellular and molecular life sciences : CMLS · 2023Article
- The interaction of steroids with phospholipid bilayers and membranes.Biophysical reviews · 2022Review
- A GlutamateThe Journal of pharmacology and experimental therapeutics · 2021Article
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Site of Action of Brain Neurosteroid Pregnenolone Sulfate at the N-Methyl-D-Aspartate Receptor.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- 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
- Rationalizing Steroid Interactions with Lipid Membranes: Conformations, Partitioning, and Kinetics.ACS central science · 2018Article
- Mechanism and properties of positive allosteric modulation of N-methyl-d-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives.Neuropharmacology · 2017Article
- A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors.Scientific reports · 2017Article
- Lens Biology is a Dimension of Neurobiology.Neurochemical research · 2017Review
- Chimeric Glutamate Receptor Subunits Reveal the Transmembrane Domain Is Sufficient for NMDA Receptor Pore Properties but Some Positive Allosteric Modulators Require Additional Domains.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
- Bidirectional Effect of Pregnenolone Sulfate on GluN1/GluN2A N-Methyl-D-Aspartate Receptor Gating Depending on Extracellular Calcium and Intracellular Milieu.Molecular pharmacology · 2015Article
- Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway.Translational psychiatry · 2015Article
- Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator.Molecular pharmacology · 2014Article
- Pregnenolone sulfate as a modulator of synaptic plasticity.Psychopharmacology · 2014Review
- 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.Molecular pharmacology · 2013Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
NMDA receptor (NMDAR)-mediated excitatory synaptic transmission plays a critical role in synaptic plasticity and memory formation, whereas its dysfunction may underlie neuropsychiatric and neurodegenerative diseases. The neuroactive steroid pregnenolone sulfate (PS) acts as a cognitive enhancer in impaired animals, augments LTP in hippocampal slices by enhancing NMDAR activity, and may participate in the reduction of schizophrenia's negative symptoms by systemic pregnenolone. We report that the effects of PS on NMDAR function are diverse, varying with subunit composition and NR1 splice variant. While PS potentiates NR1-1a/NR2B receptors through a critical steroid modulatory domain in NR2B that also modulates tonic proton inhibition, potentiation of the NMDA response is not dependent upon relief of such inhibition, a finding that distinguishes it from spermine. In contrast, the presence of an NR2A subunit confers enhanced PS-potentiation at reduced pH, suggesting that it may indeed act like spermine does at NR2B-containing receptors. Additional tuning of the NMDAR response by PS comes via the N-terminal exon-5 splicing insert of NR1-1b, which regulates the magnitude of proton-dependent PS potentiation. For NR2C- and NR2D-containing receptors, negative modulation at NR2C receptors is pH-independent (like NR2B) while negative modulation at NR2D receptors is pH-dependent (like NR2A). Taken together, PS displays a rich modulatory repertoire that takes advantage of the structural diversity of NMDARs in the CNS. The differential pH sensitivity of NMDAR isoforms to PS modulation may be especially important given the emerging role of proton sensors to both learning and memory, as well as brain injury.
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Registered trials
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