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
This article analyzes in atomistic detail binding of orthosteric ligands to the muscarinic receptors.
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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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Publications
Randáková, Alena - Rudajev, Vladimír - Doležal, Vladimír - Boulos, J. - Jakubík, Jan
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Novel long‐acting antagonists of muscarinic ACh receptors
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British Journal of Pharmacology 2018, roč. 175, 10, p. 1731-1743
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IF = 6.810
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Randáková, Alena - Dolejší, Eva - Rudajev, Vladimír - Zimčík, Pavel - Doležal, Vladimír - El-Fakahany, E. E. - Jakubík, Jan
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Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline
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Neuropharmacology 2018, roč. 133, May 1, p. 129-144
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IF = 4.249
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Boulos, J. F. - Jakubík, Jan - Boulos, J. M. - Randáková, Alena - Momirov, J.
Synthesis of novel and functionally selective non‐competitive muscarinic antagonists as chemical probes
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Chemical Biology & Drug Design 2018, roč. 91, 1, p. 93-104
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IF = 2.328
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doi
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Jakubík, Jan - Randáková, Alena - Zimčík, Pavel - El-Fakahany, E. E. - Doležal, Vladimír
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Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors
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Scientific Reports. 2017, roč. 7, Jan 16, článku 40381
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IF = 4.122
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doi
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Lyukmanova, E. N. - Shulepko, M. A. - Shenkarev, Z. O. - Bychkov, M. L. - Paramonov, A. S. - Chugunov, A. O. - Kulbatskii, D. S. - Arvaniti, M. - Dolejší, Eva - Schaer, T. - Arseniev, A. S. - Efremov, R. G. - Thomsen, M. S. - Doležal, Vladimír - Bertrand, D. - Dolgikh, D. A. - Kirpichnikov, M. P.
Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors
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Scientific Reports. 2016, roč. 6, Aug 3, p. 30698
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IF = 4.259
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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 = 4.083
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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 = 4.504
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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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doi
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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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doi
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Jakubík, Jan - El-Fakahany, E. E. - Doležal, Vladimír
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Towards predictive docking at aminergic G-protein coupled receptors
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Journal of Molecular Modeling. 2015, Vol. 21, 11, p. 284
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IF = 1.438
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doi
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Lyukmanova, E. N. - Shenkarev, Z. O. - Shulepko, M. A. - Paramonov, A. S. - Chugunov, A. O. - Janíčková, Helena - Dolejší, Eva - Doležal, Vladimír - Utkin, Y.N. - Tsetlin, V.I. - Arseniev, A. S. - Efremov, R. G. - Dolgikh, D. A. - Kirpichnikov, M. P.
Structural Insight into Specificity of Interactions between Nonconventional Three-finger Weak Toxin from Naja kaouthia (WTX) and Muscarinic Acetylcholine Receptors
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Journal of Biological Chemistry. 2015, Vol. 290, 39, p. 23616-23630
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IF = 4.258
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doi
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Janíčková, Helena - Rudajev, Vladimír - Dolejší, Eva - Koivisto, H. - Jakubík, Jan - Tanila, H. - El-Fakahany, E. E. - Doležal, Vladimír
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Lipid-Based Diets Improve Muscarinic Neurotransmission in the Hippocampus of Transgenic APPswe/PS1dE9 Mice
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Current Alzheimer Research. 2015, Vol. 12, 10, p. 923-931
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IF = 3.145
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doi
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Šantrůčková, Eva - Doležal, Vladimír - El-Fakahany, E. E. - Jakubík, Jan
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Long-Term Activation upon Brief Exposure to Xanomleline Is Unique to M1 and M4 Subtypes of Muscarinic Acetylcholine Receptors
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PLoS ONE 2014, roč. 9, 2, e88910. ISSN 1932-6203.
IF = 3.234
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Jakubík, Jan - Zimčík, Pavel - Randáková, Alena - Fuksová, Květoslava - El-Fakahany, E. E. - Doležal, Vladimír
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Molecular Mechanisms of Methoctramine Binding and Selectivity at Muscarinic Acetylcholine Receptors
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Molecular Pharmacology 2014, roč. 86, 2, p. 180-192. ISSN 0026-895X.
IF = 4.128
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doi
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Jakubík, Jan - Šantrůčková, Eva - Randáková, Alena - Janíčková, Helena - Zimčík, Pavel - Rudajev, Vladimír - Michal, Pavel - El-Fakahany, E. E. - Doležal, Vladimír
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Outline of therapeutic interventions with muscarinic receptor-mediated transmission
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Physiological Research 2014, roč. 63, suppl.1, s177-s189. ISSN 0862-8408.
IF = 1.293
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Janíčková, Helena - Rudajev, Vladimír - Zimčík, Pavel - Jakubík, Jan - Tanila, H. - El-Fakahany, E. E. - Doležal, Vladimír
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Uncoupling of M1 muscarinic receptor/G-protein interaction by amyloid beta(1-42)
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Neuropharmacology, 2013, Vol. 67, April, p. 272-283
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IF = 4.114
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doi
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Jakubík, Jan - Randáková, Alena - Doležal, Vladimír
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On homology modeling of the M-2 muscarinic acetylcholine receptor subtype
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Journal of Computer-Aided Molecular Design, 2013, Vol. 27, 6, p. 525-538
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IF = 3.172
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Boulos, J. - Jakubík, Jan - Randáková, Alena - Avila, C.
Synthesis of N-Substituted Piperidine Salts as Potential Muscarinic Ligands for Alzheimer's Applications
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Journal of Heterocyclic Chemistry, 2013, Vol. 50, 6, p. 1363-1367
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IF = 1.224
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Savelkoul, P.J.M. - Janíčková, Helena - Kuipers, A.A.M. - Hageman, R.J.J. - Kamphuis, P.J. - Doležal, Vladimír - Broersen, L.M.
A specific multi-nutrient formulation enhances M1 muscarinic acetylcholine receptor responses in vitro
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Journal of Neurochemistry, 2012, Vol. 120, 4, p. 631-640
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IF = 3.973
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doi
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Kučerová, Lucie - Brož, Václav - Fleischmannová, Jana - Šantrůčková, Eva - Sidorov, Roman - Doležal, Vladimír - Žurovec, Michal
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Characterization of the Drosophila adenosine receptor: the effect of adenosine analogs on cAMP signaling in Drosophila cells and their utility for in vivo experiments
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Journal of Neurochemistry, 2012, Vol. 121, 3, p. 383-395
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IF = 3.973
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doi
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Lyukmanova, E. N. - Shenkarev, Z. O. - Shulepko, M. A. - Mineev, K. S. - D´Hoedt, D. - Kasheverov, I. E. - Filkin, S. Yu. - Krivolapova, A. P. - Janíčková, Helena - Doležal, Vladimír - Dolgikh, D. A. - Arseniev, A. S. - Bertrand, D. - Tsetlin, V.I. - Kirp
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NMR Structure and Action on Nicotinic Acetylcholine Receptors of Water-soluble Domain of Human LYNX1
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Journal of Biological Chemistry, 2011, Vol. 286, 12, p. 10618-10627
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IF = 4.773
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Jakubík, Jan - Janíčková, Helena - Randáková, Alena - El-Fakahany, E. E. - Doležal, Vladimír
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Subtype Differences in Pre-Coupling of Muscarinic Acetylcholine Receptors
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PLoS ONE, 2011, Vol. 6, 11, e27732
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IF = 4.092
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Jakubík, Jan - Janíčková, Helena - El-Fakahany, E. E. - Doležal, Vladimír
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Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy
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British Journal of Pharmacology, 2011, Vol. 162, 5, p. 1029-1044
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IF = 4.409
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Machová, Eva - Rudajev, Vladimír - Smyčková, Helena - Koivisto, H. - Tanila, H. - Doležal, Vladimír
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Functional cholinergic damage develops with amyloid accumulation in young adult APPswe/PS1dE9 transgenic mice
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Neurobiology of Disease, 2010, Vol. 38, 1, p. 27-35
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IF = 5.121
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Grant, M.K.O. - Noetzel, M.J. - De Lorme, K.C. - Jakubík, Jan - Doležal, Vladimír - El-Fakahany, E. E.
Pharmacological Evaluation of the Long-Term Effects of Xanomeline on the M1 Muscarinic Acetylcholine Receptor
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PLoS ONE, 2010, Vol. 5, 12, e15722-16
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IF = 4.411
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Mordvintsev, D.Y. - Polyak, Y.L. - Rodionov, D.I. - Jakubík, Jan - Doležal, Vladimír - Karlsson, E. - Tsetlin, V.I. - Utkin, Y.N.
Weak toxin WTX from Naja kaouthia cobra venom interacts with both nicotinic and muscarinic acetylcholine receptors
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FEBS Journal, 2009, Vol. 276, 18, p. 5065-5075
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IF = 3.042
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doi
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Michal, Pavel - Rudajev, Vladimír - El-Fakahany, E. E. - Doležal, Vladimír
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Membrane cholesterol content influences binding properties of muscarinic M2 receptors and differentially impacts activation of second messenger pathways
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European Journal of Pharmacology, 2009, Vol. 606, 1-3, p. 50-60
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IF = 2.585
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doi
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Machová, Eva - O´Regan, S. - Newcombe, J. - Meunier, F. M. - Prentice, J. - Dove, R. - Lisá, Věra - Doležal, Vladimír
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Detection of choline transporter-like 1 protein CTL1 in neuroblastoma × glioma cells and in the CNS, and its role in choline uptake
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Journal of Neurochemistry, 2009, Vol. 110, 4, p. 1297-1309
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IF = 3.999
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Bouřová, Lenka - Stöhr, Jiří - Lisý, Václav - Rudajev, Vladimír - Novotný, Jiří - Svoboda, Petr
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G-protein activity in Percoll-purified plasma membranes, bulk plasma membranes, and low-density plasma membranes isolated from rat cerebral cortex
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Medical Science Monitor, 2009, Vol. 15, 4, BR111-BR122
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IF = 1.543
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Machová, Eva - Jakubík, Jan - Michal, Pavel - Oksman, M. - Iivonen, H. - Tanila, H. - Doležal, Vladimír
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Impairment of muscarinic transmission in transgenic APPswe/PS1dE9 mice
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Neurobiology of Aging, 2008, Vol. 29, 3, p. 368-378
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IF = 5.959
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doi
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Drastichová, Zdeňka - Bouřová, Lenka - Lisý, Václav - Hejnová, L. - Rudajev, Vladimír - Stöhr, Jiří - Durchánková, Dana - Ostašov, Pavel - Teisinger, Jan - Soukup, Tomáš - Novotný, Jiří - Svoboda, Petr
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Subcellular redistribution of trimeric G-proteins – potential mechanism of desensitization of hormone response: internalisation, solubilization, down-regulation
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Physiological Research, 2008, Vol. 57, Suppl.3, S1-S10
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IF = 1.653
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Michal, Pavel - El-Fakahany, E. E. - Doležal, Vladimír
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Muscarinic M2 receptors directly activate Gq/11 and Gs G-proteins
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Journal of Pharmacology and Experimental Therapeutics, 2007, Vol. 320, 2, p. 607-614
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IF = 4.003
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Machová, Eva - Jakubík, Jan - El-Fakahany, E. E. - Doležal, Vladimír
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Wash-Resistantly Bound Xanomeline Inhibits Acetylcholine Release by Persistent Activation of Presynaptic M2 and M4 Muscarinic Receptors in Rat Brain
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Journal of Pharmacology and Experimental Therapeutics, 2007, Vol. 322, 1, p. 316-323
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IF = 4.003
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Department of Neurochemistry
Department of Neurochemistry
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
Acetylcholine (ACh) is synthesized from choline and acetylcoenzyme A (AcCoA) by cholineacetyl transferase (ChAT) in cytoplasm of synaptic ending of neuron. ACh is transported into vesicles by vesicular acetylcholin transporter (VAChT) where it is stored untill release. Upon arrival of the signal in form of action potential to the synaptic ending vesicles fuse with plasma membrane and ACh is released to synaptic cleft. On post-synaptic membrane ACh either opens non selective cation channels - nicotinic receptors (NAChR) - or activates G protein coupled muscarinic receptors (MAChR). ACh may regulates its release via interaction with presynaptic MAChR. Action of ACh is terminated by acetylcholine esterase that cleaves it to inactive choline and acetate. Choline is transported back by to synaptic ending by choline transporter (ChT).
