We study the physiology, biochemistry and pharmacology of cholinergic neurons at molecular level. In our study we mainly employ cell lines but we also use animal models. Our research is focused mainly on these topics:
- Biochemical physiology and pharmacology of cholinergic neurons. Development and differentiation of cholinergic neurons. Synthesis, storage, and release of acetylcholine. Presynaptic regulation of acetylcholine release.
- Cholinergic mechanisms in pathogenesis of Alzheimer´s disease. Influence of beta-amyloid on acetylcholine metabolism and muscarinic transmission.
- Molecular pharmacology of muscarinic receptors. Allosteric modulation of receptor activation. Interaction of muscarinic receptors with G-proteins. Modeling of muscarinic receptor signal transduction.
Projects
The European collaborative LipiDiDiet project in the Seventh framework programme addresses the impact of nutritional lipids on neuronal and cognitive performance in aging, Alzheimer’s disease and vascular dementia. This is based on previous observations that lipids change the risk for dementia.
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Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor of Alzheimer’s disease (AD). The overall objective of this project is to investigate the cellular and molecular mechanisms underlying the neuronal and synaptic effects of apoE4 and their neuronal specificity.
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Ectopic agonists represent a new class of drugs that bind out of the orthosteric site and display unique functional selectivity through mechanisms yet to be defined. We perform a detailed analysis of receptor activation induced by ectopic and classical agonists with the aim to reveal molecular mechanisms underlying functional selectivity.
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Achievements
Dr. Jan Jakubik Institute of Physiology Academy of Sciences and professor. Jaromir Mysliveček Institute of Physiology 1st Faculty of Medicine were approached to write the current list of methods that are used in research of muscarinic receptor as part of a Neuromethods series published by Springer.
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Procedure described in this paper represents a possible way to predict interactions of antagonists with aminergic GPCRs.
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Even short-term feeding of transgenic mice with chow containing specific lipid-based dietary supplements can influence markers of cholinergic synapses and rectify impaired muscarinic signal transduction that develops in transgenic mice.
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Both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site.
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Our results show commonalities of xanomeline reversible and wash-resistant binding and short-time activation among the five muscarinic receptor subtypes. However long-term receptor activation takes place in full only at hM1 and hM4 receptors. Moreover xanomeline displays higher efficacy at hM1 and hM4 receptors in primary phasic intracellular calcium release. These findings suggest the existence of particular activation mechanisms specific to these two receptors.
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Publications
Koivisto, H. - Leinonen, H. - Puurula, M. - Hafez, H. S. - Barrera Alquicer, Glenda - Stridh, M. L. - Waagepetersen, H. S. - Tiainen, M. - Soininen, P. - Zilberter, Y. - Tanila, H.
Chronic Pyruvate Supplementation Increases Exploratory Activity and Brain Energy Reserves in Young and Middle-Aged Mice
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Frontiers in Aging Neuroscience. 2016, roč. 8, Mar 16, p. 41
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IF = 4.348
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Dolejší, Eva - Liraz, O. - Rudajev, Vladimír - Zimčík, Pavel - Doležal, Vladimír - Michaelson, D. M.
Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice
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Journal of Neurochemistry. 2016, roč. 136, 3, p. 503-509
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IF = 3.842
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Roubalová, Lenka - Vošahlíková, Miroslava - Brejchová, Jana - Sýkora, Jan - Rudajev, Vladimír - Svoboda, Petr
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High Efficacy but Low Potency of delta-Opioid Receptor-G Protein Coupling in Brij-58-Treated, Low-Density Plasma Membrane Fragments
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PLoS ONE. 2015, Vol. 10, 8, e0135664
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IF = 3.057
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Randáková, Alena - Dolejší, Eva - Rudajev, Vladimír - Zimčík, Pavel - Doležal, Vladimír - El-Fakahany, E. E. - Jakubík, Jan
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Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms
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Pharmacological Research. 2015, Vol. 97, Jul 2015, p. 27-39
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IF = 4.816
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Michal, Pavel - El-Fakahany, E. E. - Doležal, Vladimír
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Changes in Membrane Cholesterol Differentially Influence Preferential and Non-preferential Signaling of the M1 and M3 Muscarinic Acetylcholine Receptors
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Neurochemical Research. 2015, Vol. 40, 10, p. 2068-2070
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IF = 2.472
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Department of Neurochemistry, July 2016
Model of postsynaptic membrane. βA fibril, ACh - acetylcholine, APP - amyloid precursor protein, Go G-protein, Kir - inward rectifying potassium channel, M2 muscarinic receptor
