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.
Job vacancies:.Leader of the Department of Neurochemistry
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
Publications
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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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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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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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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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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doi
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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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doi
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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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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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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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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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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).
