ReviewNeurosteroid modulation of N-methyl-d-aspartate receptors: Molecular mechanism and behavioral effects
Highlights
► The mechanism of modulation of NMDA receptors by steroids is shown. ► Steroids inhibiting NMDA receptors are use-dependent. ► Steroids potentiating NMDA receptors are disuse-dependent. ► The comparison of action of steroids on NMDA and GABAA receptors. ► The action of steroids in animal models of human diseases.
Introduction
Steroids are a family of organic compounds commonly found in prokaryotic and eukaryotic organisms, including plants and animals, where they play critical structural and functional roles. They are a common component of cell membranes, where they play key roles in the organization of subcellular compartments. Other steroids produced by specialized tissues, called steroid hormones, have various metabolic effects in vertebrates [1]. This review focuses on a specific group of steroids known as neurosteroids (Fig. 1), which are produced locally in the mammalian central nervous system independently of peripheral glands [2]. Initial studies of Selye showed that the administration of the steroid allopregnanolone has acute and only temporal anesthetic effects [3]. Many recent studies suggest that neurosteroids play important roles in neuronal circuit maturation via autocrine and/or paracrine actions. It is believed that neurosteroids execute their effects by modulating the activity of different membrane receptors, including the glutamatergic ionotropic receptors: (2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA), kainate and N-methyl-d-aspartate (NMDA) receptors.
The aim of this review is to sum up the results of experiments designed to (i) study the molecular mechanisms underlying the modulation of NMDA receptor function by neurosteroids and related steroid compounds and (ii) study the action of neurosteroids in animal models of human diseases.
Section snippets
NMDA receptor
Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) of vertebrates. NMDA receptors, which are named after the specific agonist NMDA, are a subtype of glutamate ionotropic receptors. These receptors are thought to be localized postsynaptically in excitation synapses in the CNS; however, they can also be found presynaptically, extrasynaptically, and in glial cells [4]. NMDA receptors play crucial roles in synaptic plasticity such as long-term potentiation and
Neurosteroid inhibition of NMDA receptors – mechanism of action
Pregnanolone sulfate (3α5βS or 20-oxo-5β-pregnan-3α-yl sulfate) (Fig. 1B) is a typical representative member of a large group of steroids that have inhibitory effects on GABAA, AMPA, kainate, and NMDA receptors (see the Table 1, Table 2) [24], [25]. Concerning the NMDA receptors, initial experiments demonstrated that the mechanism of 3α5βS action is not competitive inhibition with agonist glutamate [25]. Further measurements showed that the degree of inhibition of NMDA receptor currents by
Concentration of neurosteroids having modulatory effects on NMDA receptors in the nervous system
Two neurosteroids, PS and 3α5βS, discussed in previous sections for their abilities to modulate NMDA receptor responses, are present in the mammalian CNS. Many studies suggest that the concentrations of neurosteroids in the CNS (e.g., 3α-hydroxy-5α-pregnan-20-one (3α5α, allopregnanolone), 20-oxo-5β-pregnan-3α-ol (3α5β, pregnanolone) pregnenolone, and PS) may depend on specific physiological or pathophysiological conditions such as stress, depression, or neurodegenerative diseases [38], [53],
Comparison of the effects of steroids at NMDA and GABA receptors
It has been shown that neurosteroids also modulate γ-aminobutyric acid type A (GABAA) receptors. Similarly, as in the case of NMDA receptors, neurosteroids can both potentiate and inhibit the activity of GABAA receptors. Apart from these allosteric modulatory effects, certain steroids can directly activate GABAA receptors [74], [75]; this feature is called the GABA-mimetic effect.
The configuration and substitution on the chiral carbon C3 and configuration on C5 (rings A and B fusion) in the
Actions of neurosteroids in animal models of human diseases
Recent evidence of fast molecular actions of neurosteroids on the ionotropic receptors, discussed above, give rise to an appealing question about their physiological role in the regulation of behavioral phenomena and their potential therapeutic benefit both in animal models and clinical treatment. Despite similar basic chemical structures, neuroactive steroids exert very complex and often biphasic effects on animal behavior, including actions in the animal models of nervous system disorders.
Summary and future prospects
NMDA together with AMPA and kainate receptors comprise the major excitatory system in the mammalian central nervous system. An increasing number of studies support a direct or indirect role (particularly of NMDA receptors) in various human diseases. Thus, NMDA receptors represent a promising target for affecting neuronal function. However, surprisingly few compounds modulating the properties of NMDA receptors at the molecular and behavioral level are clinically used.
In recent years, there has
Acknowledgments
This work was supported by the Grant Agency of the Czech Republic (309/07/0271, 309/08/H079, P303/11/0075 and P303/11/P391), Research Project of the AS CR (AV0Z 50110509, Z4 055 0506), Ministry of Education, Youth and Sports of the Czech Republic (1M0517 MSMT CR and LC554) and by IGA Ministry of Health NS10365.
References (107)
- et al.
Neurosteroids: a new brain function?
J Steroid Biochem Mol Biol
(1990) - et al.
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors
Neuron
(1994) - et al.
NMDA receptor subunits: diversity, development and disease
Curr Opin Neurobiol
(2001) - et al.
The effect of competitive antagonist chain length on NMDA receptor subunit selectivity
Neuropharmacology
(2005) - et al.
Sulfated and unsulfated steroids modulate gamma-aminobutyric acid A receptor function through distinct sites
Brain Res
(1999) Memantine is a potent blocker of N-methyl-d-aspartate (NMDA) receptor channels
Eur J Pharmacol
(1989)- et al.
Ketamine and phencyclidine cause a voltage-dependent block of responses to l-aspartic acid
Neurosci Lett
(1985) - et al.
Sulfated steroids as endogenous neuromodulators
Pharmacol Biochem Behav
(2006) - et al.
Differential regulation of ionotropic glutamate receptors
Biophys J
(2007) - et al.
Distinct effect of pregnenolone sulfate on NMDA receptor subtypes
Neuropharmacology
(2001)
Subtype-dependence of N-methyl-d-aspartate receptor modulation by pregnenolone sulfate
Neuroscience
Effects of PKC activation and receptor desensitization on neurosteroid modulation of GABA(A) receptors
Brain Res Mol Brain Res
Pregnenolone sulfate modulation of N-methyl-d-aspartate receptors is phosphorylation dependent
Neuroscience
Neurosteroid-induced enhancement of glutamate transmission in rat hippocampal slices
Neurosci Lett
Neurosteroids enhance spontaneous glutamate release in hippocampal neurons
J Biol Chem
Neurosteroids allosterically modulate the ion pore of the NMDA receptor consisting of NR1/NR2B but not NR1/NR2A
Biochem Biophys Res Commun
Simultaneous quantification of GABAergic 3alpha,5alpha/3alpha,5beta neuroactive steroids in human and rat serum
Steroids
Capillary liquid chromatography combined with tandem mass spectrometry for the study of neurosteroids and oxysterols in brain
Neurochem Int
Pregnenolone and its sulfate ester in the rat brain
Brain Res
Studies on neurosteroids XV. Development of enzyme-linked immunosorbent assay for examining whether pregnenolone sulfate is a veritable neurosteroid
J Pharm Biomed Anal
Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain
J Lipid Res
Pregnenolone sulfate in the brain: a controversial neurosteroid
Neurochem Int
Analysis of pregnenolone and dehydroepiandrosterone in rodent brain: cholesterol autoxidation is the key
J Lipid Res
Sex steroids and 5-en-3 beta-hydroxysteroids in specific regions of the human brain and cranial nerves
J Steroid Biochem
Neurosteroid modulation of recombinant ionotropic glutamate receptors
Brain Res
Synthesis of C3, C5, and C7 pregnane derivatives and their effect on NMDA receptor responses in cultured rat hippocampal neurons
Steroids
Neurosteroid modulation of GABAergic neurotransmission in the central amygdala: a role for NMDA receptors
Neurosci Lett
17 Beta-estradiol protects against NMDA-induced excytotoxicity by direct inhibition of NMDA receptors
Brain Res
Neurosteroid binding sites on GABA(A) receptors
Pharmacol Ther
Conserved site for neurosteroid modulation of GABA A receptors
Neuropharmacology
3Beta-hydroxysteroids and pregnenolone sulfate inhibit recombinant rat GABA(A) receptor through different channel property
Eur J Pharmacol
Neurosteroids and behavior
Int Rev Neurobiol
The neuroactive steroid 3-alpha-ol-5-beta-pregnan-20-one hemisuccinate, a selective NMDA receptor antagonist improves behavioral performance following spinal cord ischemia
Brain Res
Mechanisms of neurosteroid interactions with GABA(A) receptors
Pharmacol Ther
Steroids, neuroactive steroids and neurosteroids in psychopathology
Prog Neuropsychopharmacol Biol Psychiatry
Cellular and behavioural effects of a new steroidal inhibitor of the N-methyl-d-aspartate receptor 3alpha5beta-pregnanolone glutamate
Neuropharmacology
Dehydroepiandrosterone sulfate prevents ischemia-induced impairment of long-term potentiation in rat hippocampal CA1 by up-regulating tyrosine phosphorylation of NMDA receptor
Neuropharmacology
Neurosteroid consumption has anxiolytic effects in mice
Pharmacol Biochem Behav
The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory
Cell
Dehydroepiandrosterone sulfate improves memory in aging mice
Brain Res
The effects of pregnenolone sulfate and ethylestrenol on retention of a passive avoidance task
Brain Res
Effects of non-competitive AMPA receptor antagonists injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy
Neuropharmacology
Convulsant actions of the neurosteroid pregnenolone sulfate in mice
Brain Res
Nuclear receptor coregulators: cellular and molecular biology
Endocr Rev
Anesthetic effect of steroid hormones
Proc Soc Exp Biol Med
Biology of the NMDA receptor
The glutamate receptor ion channels
Pharmacol Rev
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor
Nature
Molecular basis of NMDA receptor functional diversity
Eur J Neurosci
Subunit counting in membrane-bound proteins
Nat Methods
Cited by (56)
Identification of N-methyl-D-aspartate receptor antagonists using the rat postnatal mixed cortical and hippocampal neurons
2022, European Journal of PharmacologyCitation Excerpt :The goal of this work was to identify an optimal neuronal in vitro model for NMDA antagonist project and to implement it into the screening cascade as a secondary screen (Fig. 1.) that would validate the hits identified in the primary screen i.e., HEK 293 cells transfected with GluN1-1a/GluN2B/GFP genes, patch-clamp technique (Vyklicky et al., 2015; Korinek et al., 2011; Petrovic et al., 2005). We hypothesized that using mixed cortical and hippocampal primary rat postnatal neurons may be optimal for screening and characterization of the neuroprotective potential of NMDAR antagonists.
Visualizing pregnenolone sulfate-like modulators of NMDA receptor function reveals intracellular and plasma-membrane localization
2019, NeuropharmacologyCitation Excerpt :Effects on NMDARs depend on both subunit composition and on steroid structure. Pregnane sulfates produce mainly NMDAR inhibition, and pregnenolone sulfate (PREGS) induces potentiation (Korinek et al., 2011; Malayev et al., 2002; Park-Chung et al., 1994, 1997). Although modulators of NMDARs may have clinical utility (Abdallah et al., 2015; Collingridge et al., 2013; Lai et al., 2011; Sun et al., 2015; Vyklicky et al., 2016), our understanding of the effects of PREGS at these receptors remains limited, including basic structure-activity information (Burnell et al., 2018).
Role of Steroid Therapy after Ischemic Stroke by N-Methyl-D-Aspartate Receptor Gene Regulation
2018, Journal of Stroke and Cerebrovascular DiseasesModulation of GABA and glycine receptors in rat pyramidal hippocampal neurones by 3α5β-pregnanolone derivatives
2018, Neurochemistry International