Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons

  title={Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons},
  author={Robert P. Irwin and Nicholas J. Maragakis and Michael A. Rogawski and Robert H. Purdy and David H. Farb and Steven M. Paul},
  journal={Neuroscience Letters},

Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism

The inhibition of Ca2+ channel currents by endogenous brain steroids was examined in freshly dissociated pyramidal neurons from the adult guinea pig hippocampal CA1 region, suggesting that the steroid binding site can only be accessed extracellularly.

Corticosterone acutely prolonged N‐methyl‐d‐aspartate receptor‐mediated Ca2+ elevation in cultured rat hippocampal neurons

The results imply that high levels of CORT induce a rapid and non‐genomic prolongation of NMDA receptor‐mediated Ca2+ elevation, probably via putative membrane surface receptors for CORT in the hippocampal neurons.

Neurosteroids Enhance Spontaneous Glutamate Release in Hippocampal Neurons

The results suggest that PREGS increases spontaneous glutamate release via activation of a presynaptic Gi/o-coupled ς receptor and an elevation in intracellular Ca2+ levels.

N-methyl-D-aspartate induces a rapid, reversible, and calcium-dependent intracellular acidosis in cultured fetal rat hippocampal neurons

The ability of NMDA to alter intracellular pH (pHi) was studied in fetal rat hippocampal neurons and glia using the pH-sensitive fluorescent indicator 2′,7′-bis-(2-carboxyethyl)-5-(and-6)- carboxyfluorescein (BCECF) to suggest that the reduction in neuronal pHi induced by NMDA receptor activation may mediate some of the physiological and pathophysiological actions of glutamate.

Neurosteroid modulation of glutamate release in hippocampal neurons: lack of an effect of a chronic prenatal ethanol exposure paradigm.

Chronic prenatal ethanol exposure does not affect the basal probability of glutamate release in immature or mature hippocampal neurons, and the presynaptic actions of the neurosteroid PREGS also are unaffected by this exposure.

Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids.

Sulfated steroids are effective as modulators of ongoing glutamate-mediated synaptic transmission, which is consistent with their possible role as endogenous neuromodulators in the CNS.

Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-D-aspartate receptor.

The in vitro and in vivo neuroprotective effects of 3alpha5betaHS demonstrate that this steroid represents a new class of potentially useful therapeutic agents for the treatment of stroke and certain neurodegenerative diseases that involve over activation of NMDA receptors.



Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.

Pregnenolone sulfate specifically enhances NMDA-gated currents in spinal cord neurons, while inhibiting receptors for the inhibitory amino acids glycine and gamma-aminobutyric acid, as well as non-NMDA glutamate receptors, consistent with the hypothesis that neurosteroids such as pregnenol one sulfate are involved in regulating the balance between excitation and inhibition in the central nervous system.

Inverse modulation of gamma-aminobutyric acid- and glycine-induced currents by progesterone.

It is shown that in voltage-clamped neurons progesterone itself enhances GABA-induced chloride currents but, surprisingly, antagonizes those induced by glycine, suggesting that endogenous progester one or its metabolites may differentially modulate the inhibitory actions of these two neurotransmitters.

Characterization of steroid interactions with gamma-aminobutyric acid receptor-gated chloride ion channels: evidence for multiple steroid recognition sites.

Computer-modeling (ALLFIT analysis) of these curves suggests that these steroids and pentobarbital interact with multiple binding sites on GABAA receptor(s) as well as modulating GABA receptor-mediated 36Cl- uptake.

Synthesis, metabolism, and pharmacological activity of 3 alpha-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes.

Molecular modeling of the active steroids based on quantitative structure-activity relationships provides evidence to support the stereospecificity of the binding interactions and suggests that there may be more than one type of steroid binding site associated with the GABAA-receptor-mediated chloride ionophore.

Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.

Two metabolites of the steroid hormones progesterone and deoxycorticosterone are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons, which may explain the ability of certain steroid hormones to rapidly alter neuronal excitability.

Steroid anesthetics and naturally occurring analogs modulate the gamma-aminobutyric acid receptor complex at a site distinct from barbiturates.

The ability of several naturally occurring steroids to enhance GABA-mediated inhibition in the brain suggests the possibility of an endogenous steroid modulator of neuronal function.

Neurosteroids: oligodendrocyte mitochondria convert cholesterol to pregnenolone.

The active cholesterol side-chain cleavage mechanism, recently suggested immunohistochemically and already observed in cultures of C6 glioma cells, reinforces the concept of "neurosteroids" applied to delta 5-3 beta-hydroxysteroids previously isolated from brain.