A5014911652- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Cholinesterase and Neurodegenerative Diseases
- Receptor Mechanisms and Signaling
- Computational Drug Discovery Methods
- Lipid Membrane Structure and Behavior
- Nicotinic Acetylcholine Receptors Study
- Adrenal Hormones and Disorders
- Amino Acid Enzymes and Metabolism
- Epilepsy research and treatment
- Genetics and Neurodevelopmental Disorders
- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- Hormonal Regulation and Hypertension
- Phosphodiesterase function and regulation
- bioluminescence and chemiluminescence research
- Memory and Neural Mechanisms
- Photoreceptor and optogenetics research
- Chemical synthesis and alkaloids
- Cellular transport and secretion
- Chemical Synthesis and Analysis
- Biochemical Analysis and Sensing Techniques
- Adipose Tissue and Metabolism
- Stress Responses and Cortisol
- Glycosylation and Glycoproteins Research
Czech Academy of Sciences, Institute of Experimental Medicine
2018-2025
Czech Academy of Sciences
2015-2024
University of Defence
2024
University Hospital Hradec Králové
2024
Thomayer University Hospital
2024
Czech Academy of Sciences, Institute of Physiology
2013-2022
Institut des Maladies Génétiques Imagine
2021
Université Paris Cité
2021
Inserm
2021
McGill-Queen's University Press
2013-2016
Key points NMDA receptors (NMDARs) are tetrameric cation channels permeable to calcium; they mediate excitatory synaptic transmission in the CNS and their excessive activation can lead neurodegeneration. Although these direct contact with plasma membrane, lipid–NMDAR interactions little understood. Using cultured rat cerebellar granule cells, we show that acute chronic pretreatments resulting cell cholesterol depletion profoundly diminish NMDAR responses increase desensitization, also...
Tacrine (THA), a long withdrawn drug, is still popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity an issue must be considered drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored chemical space with 30 novel derivatives, focus low hepatotoxicity, anticholinesterase action, antagonism at GluN1/GluN2B subtype...
ABSTRACT Electron and confocal microscopy were used to observe the entry movement of polyomavirus virions artificial virus-like particles (VP1 pseudocapsids) in mouse fibroblasts epithelial cells. No visible differences adsorption internalization VP1 pseudocapsids (“empty” or containing DNA) observed. Viral entered cells internalized smooth monopinocytic vesicles, often proximity larger, caveola-like invaginations. Both “empty” vesicles derived from caveolae viral stained with...
Abstract Cholesterol is a structural component of cellular membranes particularly enriched in synapses but its role synaptic transmission remains poorly understood. We used rat hippocampal cultures and their acute cholesterol depletion by methyl-β-cyclodextrin as tool to describe the physiological glutamatergic transmission. proved be key molecule for function resulted significant reduction both NMDA receptor (NMDAR) AMPA/kainate receptor-mediated evoked excitatory postsynaptic currents...
N-methyl-D-aspartate receptors (NMDARs), glutamate-gated ion channels, mediate signaling at the majority of excitatory synapses in nervous system. Recent sequencing data for neurological and psychiatric patients have indicated numerous mutations genes encoding NMDAR subunits. Here, we present surface expression, functional, pharmacological analysis 11 de novo missense human hGluN2B subunit (P553L; V558I; W607C; N615I; V618G; S628F; E657G; G820E; G820A; M824R; L825V) located preM1, M1, M2,...
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 use-dependent voltage-independent inhibitory effect neurosteroids on NMDAR responses. The site action located at extracellular vestibule receptor’s ion channel pore accessible after receptor...
Postsynaptic N -methyl- d -aspartate receptors (NMDARs) phasically activated by presynaptically released glutamate are critical for synaptic transmission and plasticity. However, under pathological conditions, excessive activation of NMDARs tonically increased ambient contributes to excitotoxicity associated with various acute chronic neurological disorders. Here, using heterologously expressed GluN1/GluN2A GluN1/GluN2B rat autaptic hippocampal microisland cultures, we show that pregnanolone...
The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on discovery disease-modifying agents. Given complexity disease, such aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact pathophysiology more comprehensively. Herewith, we contemplated therapeutic efficacy amiridine drug acting as a cholinesterase inhibitor converting it into class MTDLs. Applying linking approach, have paired core...
Alzheimer’s disease (AD) is a complex neurodegenerative disorder with an unclear etiology. Current treatments, primarily cholinesterase (ChE) inhibitors and N-methyl-D-aspartate receptor (NMDAR) antagonists, offer only symptomatic relief. Drugs targeting one pathological condition have generated limited efficacy. Thus, combining two or more therapeutic interventions into molecule believed to provide higher benefits for the treatment of AD. In this study, we designed, synthesized,...
NMDA receptors are highly expressed in the CNS and involved excitatory synaptic transmission plasticity as well excitotoxicity. They have several binding sites for allosteric modulators, including neurosteroids, endogenous compounds synthesized by nervous tissue expected to act locally. Whole-cell patch-clamp recording from human embryonic kidney 293 cells expressing NR1-1a/NR2B revealed that neurosteroid pregnenolone sulfate (PS) (300 μ m ), when applied resting receptors, potentiates...
N-Methyl-d-aspartate (NMDA) receptors are glutamate-gated ion channels composed of NR1 and NR2 subunits. When expressed alone, the most prevalent splice variant all subunits retained in endoplasmic reticulum (ER), whereas other variants reach cell surface to varying degrees. Because similar trafficking patterns have been seen for single transmembrane domain chimeric proteins with appended C termini NMDA receptor subunits, these used as a model studying mechanisms underlying ER retention...
BACKGROUND AND PURPOSE NMDA receptors are glutamatergic ionotropic involved in excitatory neurotransmission, synaptic plasticity and excitotoxic cell death. Many allosteric modulators can influence the activity of these positively or negatively, with behavioural consequences. 20‐Oxo‐5β‐pregnan‐3α‐yl sulphate (pregnanolone sulphate; PA‐6) is an endogenous neurosteroid that inhibits neuroprotective. We tested hypothesis interaction PA‐6 plasma membrane critical for its inhibitory effect at...
NMDA receptors are ligand-gated ion channels permeable to calcium and play a critical role in excitatory synaptic transmission, plasticity, excitotoxicity. They heteromeric complexes of NR1 combined with NR2A-D and/or NR3A-B subunits that activated by glutamate glycine whose activity is modulated allosteric modulators. In this study, patch-clamp recordings from human embryonic kidney 293 cells expressing NR1/NR2 were used study the molecular mechanism endogenous neurosteroid...
NMDA receptors are glutamate-gated ion channels that play important roles in synaptic transmission and excitotoxicity. The functional receptor is thought to be a heterotetramer composed mainly of two NR1 NR2 subunits. Although it generally accepted only correctly assembled can pass the ER quality control, mechanism underlying this process not well understood. Using truncated chimeric subunits expressed heterologous cells cortical neurons, we found third membrane domains (M3) both NR2B...
Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors. Compounds with balanced inhibitory potencies the target proteins (K1578 K1599) or increased potency AChE (K1592 K1594) were studied to identify most promising pro-cognitive compound. Their effects in cholinergic...