Distributions of therapeutically promising neurosteroids in cellular membranes. (March 2017)

• Record Type: Journal Article
• Authors: Riedlová, Kamila; Nekardová, Michaela; Kačer, Petr; Syslová, Kamila; Vazdar, Mario; Jungwirth, Pavel; Kudová, Eva; Cwiklik, Lukasz
• Is Part Of: Chemistry and physics of lipids. Volume 203(2017)
• Page Start: 78
• Page End: 86
• Publication Date: 2017-03
• Subjects: Steroids -- N-Methyl-d-aspartate receptors -- Membranes -- Molecular dynamics -- Chromatography; Lipids -- Periodicals; Lipids -- Periodicals; Lipides -- Périodiques; Lipids; Periodicals; Electronic journals; 547.77
• DOI: 10.1016/j.chemphyslip.2016.12.004
• Languages: English
• ISSNs: 0009-3084

Abstract

Highlights: Pregnanolone sulfate (PAS) and pregnanolone glutamate (PAG) inhibit N -Methyl-Daspartate receptors (NMDARs). PAG is a novel synthetic steroidal inhibitor but endogenous PAS inhibits NMDARs significantly more than PAG. There is no significant difference of lipophilicity and membrane permeability between PAS and PAG. Both steroids differ significantly regarding detailed localization in bilayers and hydration of their polar groups. Abstract: Interactions of two neurosteroids, inhibiting membrane-bound N -Methyl-d -aspartate receptors, with phospholipid membranes are studied. Namely, endogenous pregnanolone sulfate is compared with pregnanolone glutamate, the latter being a novel synthetic steroidal inhibitor of these receptors with potential pharmaceutical use. Molecular-level details of steroid-phospholipid membranes interactions are scrutinized employing molecular dynamics simulations supported by quantum chemical calculations to assess steroid lipophilicity. Moreover, permeability of both species across membranes is experimentally evaluated by immobilized artificial membrane chromatography. We demonstrate that while there is no significant difference of lipophilicity and membrane permeability between the two steroids, they differ significantly regarding detailed localization in phospholipid membranes. The bulky glutamate moiety of pregnanolone glutamate is flexible and well exposed to the water phase while the sulfate group of pregnanolone sulfate is hidden in the membrane headgroup region. This dissimilarity of behavior in membranes can potentially account for the observed different activities of the two steroids toward membrane-bound N -Methyl-d -aspartate receptors.