Subtype-dependence of N-methyl-d-aspartate receptor modulation by pregnenolone sulfate

Hořák, Martin; Vlček, Kamil; Chodounská, Hana; Vyklicky, Ladislav

doi:10.1016/j.neuroscience.2005.08.058

Cited by 89 publications

(105 citation statements)

References 24 publications

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“…We have shown recently that PS, a neurosteroid structurally similar to 3␣5␤S, has a positive and negative effect on NMDA receptors and further that the structure of the extracellular M3-M4 loop of the NR2 subunit is critical for the expression of both effects (Malayev et al, 2002;Horak et al, 2004Horak et al, , 2005. To explore the molecular basis of 3␣5␤S action at NR2 subunits, which may be similar to the inhibitory effect of PS, we used a chimera (NR2A3C4A) in which the extracellular M3-M4 loop of the NR2A subunit, which is less sensitive to the inhibitory effect of 3␣5␤S, was exchanged for the homologous region of the NR2C subunit, which is more sensitive to the inhibitory effect of 3␣5␤S.…”

Section: ␣5␤s Inhibition Is Influenced By the Nmda Receptor Subunit mentioning

confidence: 99%

“…receptor subunit composition: the inhibitory effect of 3␣5␤S and PS is more pronounced at receptors containing NR2C/D subunits, and the potentiating effect of PS is more pronounced at receptors containing NR2A/B subunits (Malayev et al, 2002;Horak et al, 2005). Although the neurosteroid-binding sites at the NMDA receptor have not been identified with certainty, the data presented here for 3␣5␤S and those for PS (Jang et al, 2004;Horak et al, 2005) indicate the importance of the M3-M4 loop of the NR2 subunit that controls the sensitivity to both neurosteroid-induced potentiation and inhibition. The experimental data are compatible with a model that assumes that two separate binding sites for neurosteroids exist at the NMDA receptor: activation of the first type by 3␣5␤S and PS has an inhibitory effect, whereas activation of the second type by PS has a potentiating effect.…”

Section: Comparison Of 3␣5␤s and Ps Action At Nmda Receptorsmentioning

confidence: 99%

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20-Oxo-5β-Pregnan-3α-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor

Petrović¹,

Sedlacek²,

Hořák³

et al. 2005

J. Neurosci.

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NMDA receptors are ligand-gated ion channels permeable to calcium and play a critical role in excitatory synaptic transmission, synaptic plasticity, and excitotoxicity. They are heteromeric complexes of NR1 combined with NR2A-D and/or NR3A-B subunits that are activated by glutamate and glycine and whose activity is modulated by allosteric modulators. In this study, patch-clamp recordings from human embryonic kidney 293 cells expressing NR1/NR2 receptors were used to study the molecular mechanism of the endogenous neurosteroid 20-oxo-5␤-pregnan-3␣-yl sulfate (3␣5␤S) action at NMDA receptors. 3␣5␤S was a twofold more potent inhibitor of responses mediated by NR1/NR2C-D receptors than those mediated by NR1/NR2A-B receptors. The structure of the extracellular loop between the third and fourth transmembrane domains of the NR2 subunit was found to be critical for the neurosteroid inhibitory effect. The degree of 3␣5␤S-induced inhibition of responses to glutamate was voltage independent, with recovery lasting several seconds. In contrast, application of 3␣5␤S in the absence of agonist had no effect on the subsequent response to glutamate made in the absence of the neurosteroid. A kinetic model was developed to explain the use-dependent action of 3␣5␤S at NMDA receptors. In accordance with the model, 3␣5␤S was a less potent inhibitor of NMDA receptor-mediated EPSCs and responses induced by a short application of 1 mM glutamate than of those induced by a long application of glutamate.These results suggest that 3␣5␤S is a use-dependent but voltage-independent inhibitor of NMDA receptors, with more potent action at tonically than at phasically activated receptors. This may be important in the treatment of excitotoxicity-induced neurodegeneration.

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Section: ␣5␤s Inhibition Is Influenced By the Nmda Receptor Subunit mentioning

confidence: 99%

Section: Comparison Of 3␣5␤s and Ps Action At Nmda Receptorsmentioning

confidence: 99%

20-Oxo-5β-Pregnan-3α-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor

Petrović¹,

Sedlacek²,

Hořák³

et al. 2005

J. Neurosci.

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“…Likewise, pharmacological activation of voltage-gated Ca 2ϩ channels increases insulin secretion in the absence of glucose (52). Pregnenolone sulfate stimulation has been shown to induce an influx of Ca 2ϩ ions into neurons or pancreatic ␤-cells (5,7,12,53). Using pharmacological tools, we have shown in this study that the influx of Ca 2ϩ ions and the subsequent rise of the intracellular Ca 2ϩ concentration is absolutely essential to continue the pregnenolone sulfate-induced signaling cascade in INS-1 cells.…”

Section: Discussionmentioning

confidence: 60%

“…Likewise, both N-methyl-D-aspartate receptors and voltage-gated Ca 2ϩ channels have been identified as targets for pregnenolone sulfate in neurons. For the regulation of N-methyl-D-aspartate receptor activity by pregnenolone sulfate, it has been shown that the extracellular loop between the 3rd and 4th transmembrane domain (M3-M4 loop) of the NR2 subunit is essential to confer sensitivity of the receptor to pregnenolone sulfate (5). Accordingly, the simplest hypothesis would be that pregnenolone sulfate binds to extracellular domains of both TRPM3 and voltage-gated Ca 2ϩ channels and thereby modulates their activity.…”

Section: Discussionmentioning

confidence: 99%

“…Pregnenolone sulfate directly acts in the nervous system by modifying neurotransmission, receptor functions, and the strength of synaptic transmission (1). Stimulation with pregnenolone sulfate has been shown to exert modulatory effects on several types of receptors and ion channels including the N-methyl-D-aspartate receptor, the ␥-amino butyric acid-A receptor (1-6), voltage-gated Ca 2ϩ channels, and Kir2.3 K ϩ channels (5,(7)(8)(9). Intracerebral infusions of pregnenolone sulfate was shown to influence cognitive processes, neuronal survival, and neurogenesis (10,11).…”

mentioning

confidence: 99%

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Signal Transduction of Pregnenolone Sulfate in Insulinoma Cells

Mayer¹,

Muller²,

Mannebach

et al. 2011

Journal of Biological Chemistry

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The neurosteroid pregnenolone sulfate acts on the nervous system by modifying neurotransmission and receptor functions, thus influencing synaptic strength, neuronal survival, and neurogenesis. Here we show that pregnenolone sulfate induces a signaling cascade in insulinoma cells leading to enhanced expression of the zinc finger transcription factor Egr-1 and Egr-1-responsive target genes. Pharmacological and genetic experiments revealed that influx of Ca 2؉ ions via transient receptor potential M3 and voltage-gated Ca 2؉ channels, elevation of the cytosolic Ca 2؉ level, and activation of ERK are essential for connecting pregnenolone sulfate stimulation with enhanced Egr-1 biosynthesis. Expression of a dominant-negative mutant of Elk-1, a key regulator of gene transcription driven by a serum response element, attenuated Egr-1 expression following stimulation, indicating that Elk-1 or related ternary complex factors connect the transcription of the Egr-1 gene with the pregnenolone sulfate-induced intracellular signaling cascade elicited by the initial influx of Ca 2؉ . The newly synthesized Egr-1 was biologically active and bound under physiological conditions to the regulatory regions of the Pdx-1, Synapsin I, and Chromogranin B genes. Pdx-1 is a major regulator of insulin gene transcription. Accordingly, elevated insulin promoter activity and increased mRNA levels of insulin could be detected in pregnenolone sulfate-stimulated insulinoma cells. Likewise, the biosynthesis of synapsin I, a synaptic vesicle protein that is found at secretory granules in insulinoma cells, was stimulated in pregnenolone sulfate-treated INS-1 cells. Together, these data show that pregnenolone sulfate induces a signaling cascade in insulinoma cells that is very similar to the signaling cascade induced by glucose in ␤-cells.Steroids synthesized in the central and peripheral nervous system that are, at least in part, independent of steroidogenic gland secretion are termed neurosteroids. They include progesterone, pregnenolone, pregnenolone sulfate, and dehydroepiandrosterone. Pregnenolone sulfate directly acts in the nervous system by modifying neurotransmission, receptor functions, and the strength of synaptic transmission (1). Stimulation with pregnenolone sulfate has been shown to exert modulatory effects on several types of receptors and ion channels including the N-methyl-D-aspartate receptor, the ␥-amino butyric acid-A receptor (1-6), voltage-gated Ca 2ϩ channels, and Kir2.3 K ϩ channels (5, 7-9). Intracerebral infusions of pregnenolone sulfate was shown to influence cognitive processes, neuronal survival, and neurogenesis (10, 11). Interestingly, the molecular cell biology of ␤-cells shows remarkable similarity to that of neurons. Neuronal genes are not only expressed in neurons, but also in endocrine cells. Pancreatic ␤-cells express synaptic vesicle proteins such as synapsin I, synaptophysin or synaptotagmin, neurotransmitters, and neurotransmitter-synthesizing enzymes. In line with this, it has recently been reported that the n...

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Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

et al. 2019

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Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β‐amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.

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Subtype-dependence of N-methyl-d-aspartate receptor modulation by pregnenolone sulfate

Cited by 89 publications

References 24 publications

20-Oxo-5β-Pregnan-3α-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor

20-Oxo-5β-Pregnan-3α-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor

Signal Transduction of Pregnenolone Sulfate in Insulinoma Cells

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

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