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Statements

Subject Item
n2:RIV%2F61989592%3A15310%2F12%3A33143002%21RIV13-MSM-15310___
rdf:type
n5:Vysledek skos:Concept
rdfs:seeAlso
http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01816.x/abstract;jsessionid=AC688D0796D6A68D8D0E67DA50B1D2A7.d04t03
dcterms:description
BACKGROUND AND PURPOSE NMDA receptors are glutamatergic ionotropic receptors involved in excitatory neurotransmission, synaptic plasticity and excitotoxic cell death. Many allosteric modulators can influence the activity of these receptors positively or negatively, with behavioural consequences. 20-Oxo-5 beta-pregnan-3a-yl sulphate (pregnanolone sulphate; PA-6) is an endogenous neurosteroid that inhibits NMDA receptors and is neuroprotective. We tested the hypothesis that the interaction of PA-6 with the plasma membrane is critical for its inhibitory effect at NMDA receptors. EXPERIMENTAL APPROACH Electrophysiological recordings and live microscopy were performed on heterologous HEK293 cells expressing GluN1/GluN2B receptors and cultured rat hippocampal neurons. KEY RESULTS Our experiments showed that the kinetics of the steroid inhibition were slow and not typical of drug-receptor interaction in an aqueous solution. In addition, the recovery from steroid inhibition was accelerated by beta- and ?-cyclodextrin. Values of IC50 assessed for novel synthetic C3 analogues of PA-6 differed by more than 30-fold and were positively correlated with the lipophilicity of the PA-6 analogues. Finally, the onset of inhibition induced by C3 analogues of PA-6 ranged from use-dependent to use-independent. The onset and offset of cell staining by fluorescent analogues of PA-6 were slower than those of steroid-induced inhibition of current responses mediated by NMDA receptors. CONCLUSION AND IMPLICATIONS We conclude that steroid accumulation in the plasma membrane is the route by which it accesses a binding site on the NMDA receptor. Thus, our results provide a possible structural framework for pharmacologically targeting the transmembrane domains of the receptor. BACKGROUND AND PURPOSE NMDA receptors are glutamatergic ionotropic receptors involved in excitatory neurotransmission, synaptic plasticity and excitotoxic cell death. Many allosteric modulators can influence the activity of these receptors positively or negatively, with behavioural consequences. 20-Oxo-5 beta-pregnan-3a-yl sulphate (pregnanolone sulphate; PA-6) is an endogenous neurosteroid that inhibits NMDA receptors and is neuroprotective. We tested the hypothesis that the interaction of PA-6 with the plasma membrane is critical for its inhibitory effect at NMDA receptors. EXPERIMENTAL APPROACH Electrophysiological recordings and live microscopy were performed on heterologous HEK293 cells expressing GluN1/GluN2B receptors and cultured rat hippocampal neurons. KEY RESULTS Our experiments showed that the kinetics of the steroid inhibition were slow and not typical of drug-receptor interaction in an aqueous solution. In addition, the recovery from steroid inhibition was accelerated by beta- and ?-cyclodextrin. Values of IC50 assessed for novel synthetic C3 analogues of PA-6 differed by more than 30-fold and were positively correlated with the lipophilicity of the PA-6 analogues. Finally, the onset of inhibition induced by C3 analogues of PA-6 ranged from use-dependent to use-independent. The onset and offset of cell staining by fluorescent analogues of PA-6 were slower than those of steroid-induced inhibition of current responses mediated by NMDA receptors. CONCLUSION AND IMPLICATIONS We conclude that steroid accumulation in the plasma membrane is the route by which it accesses a binding site on the NMDA receptor. Thus, our results provide a possible structural framework for pharmacologically targeting the transmembrane domains of the receptor.
dcterms:title
Access of inhibitory neurosteroids to the NMDA receptor Access of inhibitory neurosteroids to the NMDA receptor
skos:prefLabel
Access of inhibitory neurosteroids to the NMDA receptor Access of inhibitory neurosteroids to the NMDA receptor
skos:notation
RIV/61989592:15310/12:33143002!RIV13-MSM-15310___
n5:predkladatel
n13:orjk%3A15310
n4:aktivita
n16:Z n16:P
n4:aktivity
P(1M0517), P(ED0007/01/01), P(GA203/08/1498), P(GA309/07/0271), P(GAP303/11/0075), P(GAP303/12/1464), P(IAA400550801), P(LC554), Z(AV0Z40550506), Z(AV0Z50110509), Z(MSM6198959216)
n4:cisloPeriodika
3
n4:dodaniDat
n11:2013
n4:domaciTvurceVysledku
n22:2024438
n4:druhVysledku
n20:J
n4:duvernostUdaju
n12:S
n4:entitaPredkladatele
n17:predkladatel
n4:idSjednocenehoVysledku
120844
n4:idVysledku
RIV/61989592:15310/12:33143002
n4:jazykVysledku
n21:eng
n4:klicovaSlova
fluorescent steroid analogues; pregnane analogues; recombinant receptors; patch-clamp recording; inhibition; NMDA receptor; neurosteroids
n4:klicoveSlovo
n7:fluorescent%20steroid%20analogues n7:pregnane%20analogues n7:NMDA%20receptor n7:inhibition n7:neurosteroids n7:patch-clamp%20recording n7:recombinant%20receptors
n4:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n4:kontrolniKodProRIV
[69B89A8FBFA1]
n4:nazevZdroje
British Journal of Pharmacology
n4:obor
n19:ED
n4:pocetDomacichTvurcuVysledku
1
n4:pocetTvurcuVysledku
8
n4:projekt
n6:ED0007%2F01%2F01 n6:GA309%2F07%2F0271 n6:1M0517 n6:IAA400550801 n6:GAP303%2F11%2F0075 n6:GA203%2F08%2F1498 n6:LC554 n6:GAP303%2F12%2F1464
n4:rokUplatneniVysledku
n11:2012
n4:svazekPeriodika
166
n4:tvurceVysledku
Šťastná, Eva Chodounská, Hana Vyklický, Ladislav Slaviková, Barbora Borovská, Jiřina Kapras, Vojtěch Horák, Martin Vyklický, Vojtěch
n4:wos
000303923000021
n4:zamer
n15:MSM6198959216 n15:AV0Z40550506 n15:AV0Z50110509
s:issn
0007-1188
s:numberOfPages
15
n18:doi
10.1111/j.1476-5381.2011.01816.x
n9:organizacniJednotka
15310