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

doi:10.1124/mol.113.085696

Paper

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

Published Aug 1, 2013 · Emmanuel Kostakis, Conor C. Smith, M. Jang

Molecular Pharmacology

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39

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2

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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.

Study Snapshot

Pregnenolone sulfate stimulates the trafficking of functional N-methyl D-aspartate receptors to the cell surface through a noncanonical, G protein-coupled, and Ca2+-dependent mechanism, potentially offering a new target for treating disorders linked to NMDAR hypo

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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

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References

Gi-coupled γ-aminobutyric acid-B receptors cross-regulate phospholipase C and calcium in airway smooth muscle.

GABA(B) receptors in human airway smooth muscle cells rapidly mobilize intracellular calcium stores through the synthesis of inositol phosphate and crosstalk with G(q)-coupled receptors.

Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence

Pregnenolone shows promise as a promising novel therapeutic candidate in schizophrenia, potentially improving cognitive functions and decreasing negative symptoms.

The involvement of the NMDA receptor d-serine/glycine site in the pathophysiology and treatment of schizophrenia

The NMDA receptor d-serine/glycine site plays a crucial role in schizophrenia pathogenesis and may be a promising therapeutic target for psychiatric illness.

Uncoupling the D1-N-Methyl-D-Aspartate (NMDA) Receptor Complex Promotes NMDA-Dependent Long-Term Potentiation and Working Memory

The NMDA-D1 direct protein-protein interaction plays a critical role in NMDA receptor-mediated long-term potentiation and working memory, with CaMKII playing a role in this process.

Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity.

NMDAR-mediated calcium signaling and synaptic plasticity are dynamically regulated by PKA and extracellular signals, providing a powerful mechanism for bi-directional regulation of synaptic efficacy and remodelling.

Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications

Metabotropic glutamate receptors show promise as a promising target for future drug treatment in schizophrenia by modulating NMDA receptor dysfunction and regulating excitotoxicity mechanisms.

Neuroactive steroid regulation of neurotransmitter release in the CNS: Action, mechanism and possible significance

Neuroactive steroids, such as pregnenolone and estradiol, regulate neurotransmitter release in the central nervous system, impacting brain functions and diseases.

Na,K-ATPase Activity Regulates AMPA Receptor Turnover through Proteasome-Mediated Proteolysis

Na,K-ATPase activity regulates AMPAR turnover, affecting synaptic strength and brain function through proteasome-mediated proteolysis.

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

Pregnenolone may be a promising therapeutic agent for negative symptoms and warrants further investigation for cognitive symptoms in schizophrenia patients receiving stable doses of second-generation antipsychotics.

Citations

Neurosteroids and Translocator Protein (TSPO) in neuroinflammation

Neurosteroids and TSPO targeting show potential in treating neuroinflammation, but technical limitations and complex biosynthetic pathways hinder accurate quantification and prediction.

Corticosteroids and the Pharmacological Management of Autism—An Integrative Review

Corticosteroids show promise in safely reducing symptoms of autism, including stereotypical behaviors, hyperactivity, and irritability, with no serious adverse effects observed.

Protein quality control of N-methyl-D-aspartate receptors

NMDAR protein quality control is crucial for their function and may help target therapeutic approaches to treat neurodevelopmental and neuropsychiatric disorders.

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Understanding the structure, function, and pharmacology of glutamate receptors will advance our understanding of brain function and provide new treatment opportunities for neurological diseases.

Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis

Reduction of synaptic excitatory neurotransmission underlies seizures in NMDAR antibody-mediated encephalitis, and a neurosteroid that upregulates NMDARs can potentially reduce ictal activity.