NMDA receptors have received much attention over the last few decades, due to their role in many types of neural plasticity on the one hand, and their involvement in excitotoxicity on the other hand. There is great interest in developing clinically relevant NMDA receptor antagonists that would block excitotoxic NMDA receptor activation, without interfering with NMDA receptor function needed for normal synaptic transmission and plasticity. This review summarizes current understanding of the structure of NMDA receptors and the mechanisms of NMDA receptor activation and modulation, with special attention given to data describing the properties of various types of NMDA receptor inhibition. Our recent analyses point to certain neurosteroids as NMDA receptor inhibitors with desirable properties. Specifically, these compounds show use-dependent but voltage-independent block, that is predicted to preferentially target excessive tonic NMDA receptor activation. Importantly, neurosteroids are also characterized by use-independent unblock, compatible with minimal disruption of normal synaptic transmission. Thus, neurosteroids are a promising class of NMDA receptor modulators that may lead to the development of neuroprotective drugs with optimal therapeutic profiles.

• MeSH
• gating iontového kanálu účinky léků   MeSH
• konformace proteinů MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   MeSH
• nemoci mozku farmakoterapie   metabolismus   MeSH
• nervový přenos účinky léků   MeSH
• neurony účinky léků   metabolismus   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• receptory N-methyl-D-aspartátu chemie   účinky léků   metabolismus   ultrastruktura   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Schizophrenia (SCH) is a psychiatric disorder with a serious impact on a patient's life. This multidisciplinary project aims to determine how gene variants of the glutamate receptor complex contribute to the emergence and development of schizophrenia. (i.) Genetic analysis will be focused on candidate genes variants previously associated with SCH. The results of this analysis will be linked to individual SCH phenotypes, including clinical symptoms, central and peripheral metabolites, structural and functional neuroanatomy. (ii.) In parallel, we will analyze regulatory elements and protein encoding regions of the genes of the glutamate receptor family. (iii.) We will characterize the functional consequences of glutamate receptor complex gene variants, assessing the activity of altered NMDAR promoters, receptor trafficking, and the functional and pharmacological analysis of mutated NMDA receptors. We are convinced that this project will contribute to the identification of biological markers of SCH, effective treatment and improved patients' quality of life.

Schizofrenie (SCH) je psychiatrické onemocnění s vážným dopadem na život pacienta. Tento multidisciplinární projekt má za cíl objasnit, jakým způsobem přispívají genové varianty v komplexu glutamátového receptoru ke vzniku a rozvoji schizofrenie. (i.) Genetická analýza bude zaměřena na ty varianty kandidátních genů, které byly již dříve spojovány se SCH. Výsledky této analýzy budou propojeny s jednotlivými fenotypy SCH, včetně klinických příznaků, změn v hladinách centrálních a periferních metabolitů, strukturní a funkční neuroanatomie. (ii.) Současně budou analyzovány regulační a protein-kódující oblasti genů pro glutamátové receptory. (iii.) Dále budeme charakterizovat funkční důsledky jednotlivých genových variant v komplexu glutamátového receptoru, stanovením aktivity změněných promotorů NMDAR, transportu receptorů a funkční a farmakologickou analýzou mutovaných NMDA receptorů. Jsme přesvědčeni, že tento projekt přispěje k identifikaci biologických markérů SCH, možné účinné léčbě a zlepšení kvality života pacientů.

• MeSH
• genetické asociační studie MeSH
• glutamátové receptory MeSH
• iontové kanály MeSH
• magnetická rezonanční tomografie MeSH
• neurotransmiterové látky MeSH
• receptory N-methyl-D-aspartátu MeSH
• schizofrenie terapie   MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• psychiatrie
• biochemie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

N-methyl-D-aspartate receptors (NMDARs), glutamate-gated ion channels, mediate signaling at the majority of excitatory synapses in the nervous system. Recent sequencing data for neurological and psychiatric patients have indicated numerous mutations in genes encoding for NMDAR subunits. Here, we present surface expression, functional, and pharmacological analysis of 11 de novo missense mutations of the human hGluN2B subunit (P553L; V558I; W607C; N615I; V618G; S628F; E657G; G820E; G820A; M824R; L825V) located in the pre-M1, M1, M2, M3, and M4 membrane regions. These variants were identified in patients with intellectual disability, developmental delay, epileptic symptomatology, and autism spectrum disorder. Immunofluorescence microscopy indicated that the ratio of surface-to-total NMDAR expression was reduced for hGluN1/hGluN2B(S628F) receptors and increased for for hGluN1/hGluN2B(G820E) receptors. Electrophysiological recordings revealed that agonist potency was altered in hGluN1/hGluN2B(W607C; N615I; and E657G) receptors and desensitization was increased in hGluN1/hGluN2B(V558I) receptors. The probability of channel opening of hGluN1/hGluN2B (V558I; W607C; V618G; and L825V) receptors was diminished ~10-fold when compared to non-mutated receptors. Finally, the sensitivity of mutant receptors to positive allosteric modulators of the steroid origin showed that glutamate responses induced in hGluN1/hGluN2B(V558I; W607C; V618G; and G820A) receptors were potentiated by 59-96% and 406-685% when recorded in the presence of 20-oxo-pregn-5-en-3β-yl sulfate (PE-S) and androst-5-en-3β-yl hemisuccinate (AND-hSuc), respectively. Surprisingly hGluN1/hGluN2B(L825V) receptors were strongly potentiated, by 197 and 1647%, respectively, by PE-S and AND-hSuc. Synaptic-like responses induced by brief glutamate application were also potentiated and the deactivation decelerated. Further, we have used homology modeling based on the available crystal structures of GluN1/GluN2B NMDA receptor followed by molecular dynamics simulations to try to relate the functional consequences of mutations to structural changes. Overall, these data suggest that de novo missense mutations of the hGluN2B subunit located in membrane domains lead to multiple defects that manifest by the NMDAR loss of function that can be rectified by steroids. Our results provide an opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with hypofunction of the glutamatergic system.

• Publikační typ
• časopisecké články MeSH