Low concentrations of neuroactive steroids alter kinetics of [<sup>3</sup>H]ifenprodil binding to the NMDA receptor in rat frontal cortex

Johansson, Tobias; Frändberg, Per-Anders; Nyberg, Fred; Grevès, Pierre Le

doi:10.1038/sj.bjp.0706397

Cited by 10 publications

(17 citation statements)

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“…These results are in line with our previous experiments conducted on rat frontal cortex membranes (Johansson et al, 2005a).…”

Section: [ 3 H]ifenprodil Binding and Effects Of Ifenprodil On [Casupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

“…The altered [ prodil binding kinetics, occurring within a narrow, nanomolar range of neurosteroid concentrations, suggests an allosteric modulation of the ifenprodil binding site. In this article, we report our investigation of the functional effects of this type of modulation by measuring Ca 2ϩ influx in the CHO cell line expressing the NR1/NR2B receptor (CHO-E2) established by Uchino et al (2001 (Johansson et al, 2005b). The neurosteroid-induced effect was also confirmed in a functional assay.…”

mentioning

confidence: 99%

“…We recently published studies demonstrating that sulfated neurosteroids differentially affect the binding of ifenprodil to rat cortical membranes (Johansson and Le Greves, 2005;Johansson et al, 2005a). The altered [ prodil binding kinetics, occurring within a narrow, nanomolar range of neurosteroid concentrations, suggests an allosteric modulation of the ifenprodil binding site.…”

mentioning

confidence: 99%

“…As a result, they may regulate important processes such as plasticity (Klangkalya, 2005), memory and learning (Shimizu et al, 2000), and neuroprotection and Alzheimer's disease (Weill-Engerer et al, 2002). Pregnenolone sulfate (PS) and pregnanolone sulfate (3␣5␤S) are neurosteroids that interact at distinct sites on the NMDA receptor complex to modulate its function Horak et al, 2004;Johansson et al, 2005b). This modulation may account for some of the rapid, nongenomic effects generated by these compounds in the central nervous system.…”

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confidence: 99%

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Molecular Mechanisms for Nanomolar Concentrations of Neurosteroids at NR1/NR2B Receptors

Johansson¹,

Frändberg²,

Nyberg³

et al. 2007

J Pharmacol Exp Ther

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Neurosteroids are endogenous steroids acting in the central nervous system. They participate in synaptic plasticity, memory and learning, Alzheimer's disease, and certain drug reward. Some mechanisms behind these effects are thought to be nongenomic, e.g., they modulate the function of the N-methyl-D-aspartate (NMDA) receptor complex. In this study, we used a Chinese hamster ovary cell line stably transfected with NMDA receptor constituents NR1/NR2B, to investigate the effects of nanomolar concentrations of the neurosteroids pregnenolone sulfate (PS) and pregnanolone sulfate (3␣5␤S) Neurosteroids are endogenous steroids that act as potent modulators at NMDA and GABA A receptors (Compagnone and Mellon, 2000). As a result, they may regulate important processes such as plasticity (Klangkalya, 2005), memory and learning (Shimizu et al., 2000), and neuroprotection and Alzheimer's disease (Weill-Engerer et al., 2002). Pregnenolone sulfate (PS) and pregnanolone sulfate (3␣5␤S) are neurosteroids that interact at distinct sites on the NMDA receptor complex to modulate its function Horak et al., 2004;Johansson et al., 2005b). This modulation may account for some of the rapid, nongenomic effects generated by these compounds in the central nervous system. Neurosteroids, and sulfated neurosteroids in particular, are present at relatively low concentrations in the rat brain (Higashi et al., 2003;Liu et al., 2003). Nonetheless, when PS is administered at femtomole concentrations by intracerebroventricular injection to rodents, processes involving the NMDA receptor are affected (Flood et al., 1995;Mathis et al., 1996;Meziane et al., 1996;Weaver et al., 1997). In contrast, in electrophysiological experiments, much higher (micromolar) concentrations of the steroids are required to achieve modulatory effects on recombinant NMDA receptors (Mukai et al., 2000;Malayev et al., 2002). In these studies, PS acted as a positive allosteric modulator, stimulating the agonistinduced response of NMDA receptor complexes composed of NR1/NR2A or NR1/NR2B subunits, whereas 3␣5␤S was inhibitory (Malayev et al., 2002). Similar effects of PS and 3␣5␤S at micromolar concentrations were found when Ca 2ϩ influx was measured in CHO cells stably expressing the NMDA receptor NR1/NR2B subtype (Mukai et al., 2000).Ifenprodil, a noncompetitive antagonist of the NMDA receptor that is selective for the NR2B subunit (Chenard and Menniti, 1999;Williams, 2001), is commonly used as a pharmacological tool. We recently published studies demonstrating that sulfated neurosteroids differentially affect the binding of ifenprodil to rat cortical membranes (Johansson and Le Greves, 2005;Johansson et al., 2005a

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“…These results are in line with our previous experiments conducted on rat frontal cortex membranes (Johansson et al, 2005a).…”

Section: [ 3 H]ifenprodil Binding and Effects Of Ifenprodil On [Casupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular Mechanisms for Nanomolar Concentrations of Neurosteroids at NR1/NR2B Receptors

Johansson¹,

Frändberg²,

Nyberg³

et al. 2007

J Pharmacol Exp Ther

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Pregnenolone sulfate as a modulator of synaptic plasticity

2014

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Rationale The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects with reliable measurements of endogenous local concentrations and pharmacological and therapeutic targets has remained elusive for over 20 years. Objectives New basic and clinical research concerning neurosteroid modulation of the central nervous system (CNS) function has emerged over the past 5 years, including important data involving pregnenolone and various neurosteroid precursors of PregS that point to a need for a critical status update. Results Highly specific actions of PregS affecting excitatory N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and the pharmacological effects of PregS on various receptors and ion channels are discussed. The discovery of a high potency (nanomolar) signal transduction pathway for PregS-induced NMDAR trafficking to the cell surface via a Ca2+- and G protein-coupled receptor (GPCR)-dependent mechanism and a potent (EC50 ~2 pM) direct enhancement of intracellular Ca2+ levels is discussed in terms of its agonist effects on long-term potentiation (LTP) and memory. Lastly, preclinical and clinical studies assessing the promnestic effects of PregS and pregnenolone toward cognitive dysfunction in schizophrenia, and altered serum levels in epilepsy and alcohol dependence, are reviewed. Conclusions PregS is present in human and rodent brain at physiologically relevant concentrations and meets most of the criteria for an endogenous neurotransmitter/neuromodulator. PregS likely plays a significant role in modulation of glutamatergic excitatory synaptic transmission underlying learning and memory, yet the molecular target(s) for its action awaits identification.

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Neurosteroids allosterically modulate the ion pore of the NMDA receptor consisting of NR1/NR2B but not NR1/NR2A

Elfverson

Linde

Grevès

et al. 2008

Biochemical and Biophysical Research Communications

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Low concentrations of neuroactive steroids alter kinetics of [³H]ifenprodil binding to the NMDA receptor in rat frontal cortex

Cited by 10 publications

References 38 publications

Molecular Mechanisms for Nanomolar Concentrations of Neurosteroids at NR1/NR2B Receptors

Molecular Mechanisms for Nanomolar Concentrations of Neurosteroids at NR1/NR2B Receptors

Pregnenolone sulfate as a modulator of synaptic plasticity

Neurosteroids allosterically modulate the ion pore of the NMDA receptor consisting of NR1/NR2B but not NR1/NR2A

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Low concentrations of neuroactive steroids alter kinetics of [3H]ifenprodil binding to the NMDA receptor in rat frontal cortex

Cited by 10 publications

References 38 publications

Molecular Mechanisms for Nanomolar Concentrations of Neurosteroids at NR1/NR2B Receptors

Molecular Mechanisms for Nanomolar Concentrations of Neurosteroids at NR1/NR2B Receptors

Pregnenolone sulfate as a modulator of synaptic plasticity

Neurosteroids allosterically modulate the ion pore of the NMDA receptor consisting of NR1/NR2B but not NR1/NR2A

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Low concentrations of neuroactive steroids alter kinetics of [³H]ifenprodil binding to the NMDA receptor in rat frontal cortex