Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule

Vyklicky, V, Krausova, B, Cerny, J, Balik, A, Zapotocky, M, Navotny, M, Lichnerova, K, Smejkalova, T, Kaniakova, M et al (2015) Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule. Scientific Reports, 5 . p. 10935. ISSN 2045-2322

[thumbnail of Version of Record - Open Access]
Preview
PDF (Version of Record - Open Access) - Published Version
Available under License Creative Commons Attribution.

1MB

Official URL: http://dx.doi.org/10.1038/srep10935

Abstract

N-methyl-D-aspartate receptors (NMDARs) mediate synaptic plasticity, and their dysfunction is implicated in multiple brain disorders. NMDARs can be allosterically modulated by numerous compounds, including endogenous neurosteroid pregnanolone sulfate. Here, we identify the molecular basis of the use-dependent and voltage-independent inhibitory effect of neurosteroids on NMDAR responses. The site of action is located at the extracellular vestibule of the receptor's ion channel pore and is accessible after receptor activation. Mutations in the extracellular vestibule in the SYTANLAAF motif disrupt the inhibitory effect of negatively charged steroids. In contrast, positively charged steroids inhibit mutated NMDAR responses in a voltage-dependent manner. These results, in combination with molecular modeling, characterize structure details of the open configuration of the NMDAR channel. Our results provide a unique opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with dysfunction of the glutamate system.


Repository Staff Only: item control page