Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Neurochem
2011 Nov 01;1193:486-96. doi: 10.1111/j.1471-4159.2011.07442.x.
Show Gene links
Show Anatomy links
A steroid modulatory domain in NR2A collaborates with NR1 exon-5 to control NMDAR modulation by pregnenolone sulfate and protons.
Kostakis E
,
Jang MK
,
Russek SJ
,
Gibbs TT
,
Farb DH
.
???displayArticle.abstract???
NMDA receptor (NMDAR)-mediated excitatory synaptic transmission plays a critical role in synaptic plasticity and memory formation, whereas its dysfunction may underlie neuropsychiatric and neurodegenerative diseases. The neuroactive steroid pregnenolone sulfate (PS) acts as a cognitive enhancer in impaired animals, augments LTP in hippocampal slices by enhancing NMDAR activity, and may participate in the reduction of schizophrenia's negative symptoms by systemic pregnenolone. We report that the effects of PS on NMDAR function are diverse, varying with subunit composition and NR1 splice variant. While PS potentiates NR1-1a/NR2B receptors through a critical steroid modulatory domain in NR2B that also modulates tonic proton inhibition, potentiation of the NMDA response is not dependent upon relief of such inhibition, a finding that distinguishes it from spermine. In contrast, the presence of an NR2A subunit confers enhanced PS-potentiation at reduced pH, suggesting that it may indeed act like spermine does at NR2B-containing receptors. Additional tuning of the NMDAR response by PS comes via the N-terminal exon-5 splicing insert of NR1-1b, which regulates the magnitude of proton-dependent PS potentiation. For NR2C- and NR2D-containing receptors, negative modulation at NR2C receptors is pH-independent (like NR2B) while negative modulation at NR2D receptors is pH-dependent (like NR2A). Taken together, PS displays a rich modulatory repertoire that takes advantage of the structural diversity of NMDARs in the CNS. The differential pH sensitivity of NMDAR isoforms to PS modulation may be especially important given the emerging role of proton sensors to both learning and memory, as well as brain injury.
Banke,
Protons trap NR1/NR2B NMDA receptors in a nonconducting state.
2005, Pubmed
Banke,
Protons trap NR1/NR2B NMDA receptors in a nonconducting state.
2005,
Pubmed
Belforte,
Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.
2010,
Pubmed
Castner,
Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex.
2007,
Pubmed
Chen,
Modulatory metaplasticity induced by pregnenolone sulfate in the rat hippocampus: a leftward shift in LTP/LTD-frequency curve.
2010,
Pubmed
Dravid,
Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block.
2007,
Pubmed
,
Xenbase
Erreger,
Zinc inhibition of rat NR1/NR2A N-methyl-D-aspartate receptors.
2008,
Pubmed
Flood,
Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures: the amygdala is by far the most sensitive.
1995,
Pubmed
Furukawa,
Subunit arrangement and function in NMDA receptors.
2005,
Pubmed
Ho,
Site-directed mutagenesis by overlap extension using the polymerase chain reaction.
1989,
Pubmed
Hollmann,
Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor.
1993,
Pubmed
,
Xenbase
Horak,
Subtype-dependence of N-methyl-D-aspartate receptor modulation by pregnenolone sulfate.
2006,
Pubmed
Ishii,
Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits.
1993,
Pubmed
,
Xenbase
Jang,
A steroid modulatory domain on NR2B controls N-methyl-D-aspartate receptor proton sensitivity.
2004,
Pubmed
,
Xenbase
Kemp,
NMDA receptor pathways as drug targets.
2002,
Pubmed
Low,
Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating.
2003,
Pubmed
,
Xenbase
Makani,
Endogenous alkaline transients boost postsynaptic NMDA receptor responses in hippocampal CA1 pyramidal neurons.
2007,
Pubmed
Malayev,
Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids.
2002,
Pubmed
,
Xenbase
Martín-García,
The neurosteroid pregnenolone sulfate neutralized the learning impairment induced by intrahippocampal nicotine in alcohol-drinking rats.
2005,
Pubmed
Marx,
Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia.
2009,
Pubmed
Masuko,
A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor: effects of spermine, protons, and ifenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein.
1999,
Pubmed
,
Xenbase
Mony,
Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential.
2009,
Pubmed
Nakagawa,
Three-dimensional structure of an AMPA receptor without associated stargazin/TARP proteins.
2006,
Pubmed
Obrenovitch,
A rapid redistribution of hydrogen ions is associated with depolarization and repolarization subsequent to cerebral ischemia reperfusion.
1990,
Pubmed
Panchenko,
Structural similarities between glutamate receptor channels and K(+) channels examined by scanning mutagenesis.
2001,
Pubmed
,
Xenbase
Park-Chung,
Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids.
1997,
Pubmed
,
Xenbase
Pauly,
Synaptic targeting of N-methyl-D-aspartate receptor splice variants is regulated differentially by receptor activity.
2005,
Pubmed
Petrovic,
20-oxo-5beta-pregnan-3alpha-yl sulfate is a use-dependent NMDA receptor inhibitor.
2005,
Pubmed
Rao,
NMDA and AMPA receptors: old channels, new tricks.
2007,
Pubmed
Schumacher,
Pregnenolone sulfate in the brain: a controversial neurosteroid.
2008,
Pubmed
Siesjö,
Extra- and intracellular pH in the brain during seizures and in the recovery period following the arrest of seizure activity.
1985,
Pubmed
Thompson,
CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.
1994,
Pubmed
Tichelaar,
The Three-dimensional Structure of an Ionotropic Glutamate Receptor Reveals a Dimer-of-dimers Assembly.
2004,
Pubmed
Trakhanov,
Ligand-free and -bound structures of the binding protein (LivJ) of the Escherichia coli ABC leucine/isoleucine/valine transport system: trajectory and dynamics of the interdomain rotation and ligand specificity.
2005,
Pubmed
Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase
Traynelis,
Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines.
1995,
Pubmed
,
Xenbase
Weaver,
Geometry and charge determine pharmacological effects of steroids on N-methyl-D-aspartate receptor-induced Ca(2+) accumulation and cell death.
2000,
Pubmed
Whittaker,
Pregnenolone sulfate induces NMDA receptor dependent release of dopamine from synaptic terminals in the striatum.
2008,
Pubmed
Zheng,
Neuroactive steroid regulation of neurotransmitter release in the CNS: action, mechanism and possible significance.
2009,
Pubmed
Zukin,
Alternatively spliced isoforms of the NMDARI receptor subunit.
1995,
Pubmed
