A5085977437- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Lipid Membrane Structure and Behavior
- Nicotinic Acetylcholine Receptors Study
- Neuropeptides and Animal Physiology
- Ion channel regulation and function
- Diet and metabolism studies
- Heart Rate Variability and Autonomic Control
- Computational Drug Discovery Methods
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Cardiac Ischemia and Reperfusion
- Hormonal Regulation and Hypertension
- Vagus Nerve Stimulation Research
- Cholinesterase and Neurodegenerative Diseases
- Signaling Pathways in Disease
- GDF15 and Related Biomarkers
- Alzheimer's disease research and treatments
- Natural product bioactivities and synthesis
Czech Academy of Sciences
2015-2025
Czech Academy of Sciences, Institute of Physiology
2015-2025
ORCID
2021
Weak toxin from Naja kaouthia (WTX) belongs to the group of nonconventional "three-finger" snake neurotoxins. It irreversibly inhibits nicotinic acetylcholine receptors and allosterically interacts with muscarinic (mAChRs). Using site-directed mutagenesis, NMR spectroscopy, computer modeling, we investigated recombinant mutant WTX analogue (rWTX) which, compared native toxin, has an additional N-terminal methionine residue. In comparison wild-type rWTX demonstrated altered pharmacological...
Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, auto/paracrine activity SLURP-2 was considered to be mediated via its interaction with α3β2 subtype nicotinic acetylcholine receptors (nAChRs). Here, we describe structure pharmacology a recombinant analogue SLURP-2. Nuclear magnetic resonance spectroscopy revealed 'three-finger' fold conserved β-structural core three protruding loops. Affinity purification using...
Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and a hallmark of disease, accentuated apoE4. This revealed that levels pre-synaptic marker, vesicular acetylcholine transporter in hippocampus corresponding electrically evoked release acetylcholine, are similar 4-month-old...
Transgenic APPswe/PS1dE9 mice modeling Alzheimer's disease demonstrate ongoing accumulation of β-amyloid fragments resulting in formation amyloid plaques that starts at the age 4-5 months. Buildup is accompanied by impairment muscarinic transmission becomes detectable this age, well before appearance cognitive deficits manifest around 12 We have recently demonstrated long-term feeding trangenic with specific isocaloric fish oil-based diets improves behavioral parameters. Now we report on...
Xanomeline (3-(Hexyloxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole) is a muscarinic agonist that considered to be functionally selective for the M1/M4 receptor subtypes. Part of xanomeline binding resistant washing. Wash-resistant activates receptors persistently, except M5 subtype. Mutation leucine 6.46 isoleucine at M1 or M4 abolished persistent activation by wash-resistant xanomeline. Reciprocal mutation made it sensitive Lowering membrane cholesterol and mutants wild...
The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated binding 20 steroidal compounds neurosteroids steroid hormones Corticosterone, progesterone some bound with affinity 100 nM or greater. established a structure-activity relationship for steroid-based allosteric modulators Further, we show that corticosterone allosterically functional response at physiologically relevant...
Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind muscarinic acetylcholine receptors allosterically modulate binding function. Using radioligand experiments we investigated mode. We show that neuroactive steroids two sites on receptors. Their affinity for the high-affinity site is about 100 nM. low-affinity 10 µM. The occurs at same as of steroid-based WIN-compounds different from common allosteric alcuronium or gallamine located between...
We mutated key amino acids of the human variant M1 muscarinic receptor that target ligand binding, activation, and receptor-G protein interaction. compared effects these mutations on action two atypical functionally preferring agonists (N-desmethylclozapine xanomeline) classical non-selective orthosteric (carbachol oxotremorine). Mutations D105 in binding site mutation D99 located out decreased affinity all tested was translated as a decrease potency accumulation inositol phosphates...
Abstract The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated binding 20 steroidal compounds neurosteroids steroid hormones Corticosterone, progesterone, some bound with an affinity 100 nM or greater. established a structure-activity relationship for steroid-based allosteric modulators Further, we show that corticosterone progesterone allosterically functional response at...