Intranet

Fyziologický ústav AV ČR

Špičková věda pro zdraví

Neurochemie

Neurochemie Schéma cholinergní synapse.

Studujeme fyziologii, biochemii a farmakologii cholinergních neuronů na molekulární úrovni. Ke studiu využíváme především buněčných linií, ale i zvířecích modelů. Zabýváme se hlavně výzkumem v těchto oblastech:

  • Biochemická fyziologie a farmakologie cholinergních neuronů. Vývoj a diferenciace cholinergních neuronů. Syntéza, skladování a uvolňování acetylcholinu. Regulace uvolňování acetylcholinu presynaptickými receptory.
  • Cholinergní mechanismy v patogenezi Alzheimerovy nemoci. Interakce mezi peptidem beta-amyloidem, acetylcholinem, muskarinovými acetylcholinovými receptory, přenosem signálu přes membránu a aktivací signálních drah.
  • Muskarinové receptory pro acetylcholin. Vazebné ortosterické a alosterické vlastnosti. Interakce s G-proteiny, modelování přenosu signálu do buňky.

Aktuální projekty

Cholinergní modulace striatem řízeného chování

Cílem projektu je za využití  myšího modelu s delecí podjednotky β2 nikotinového receptoru pro acetylcholin v GABAergních interneuronech ve striatu zjistit, jak narušení cholinergní aktivace GABAergních interneuronů ve striatu mění signalizaci a striatem řízené chování. Více

Úspěchy

Agonist-specific conformations of the M<sub>2</sub> muscarinic acetylcholine receptor assessed by molecular dynamics

Structurally diverse agonists for a given receptor induce receptor conformations specific to each structural family. These agonist-specific conformations can lead to non-uniform modulation of signalling pathways. This preferential orientation of signalling of a given receptor towards a subset of its signal transducers is termed signalling bias. This property may be employed to develop drugs that selectively produce desired effects while avoiding side effects associated with activation of unwanted signalling pathways. We modelled conformations of the M2 receptor specific to individual agonists, including the newly developed Gi-biased agonists. Více

Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline

Our new publication in journal Neuropharmacology in which we demonstrate that membrane cholesterol plays an important and subtype-specific role in activation of muscarinic acetylcholine receptors. To our knowledge, this is the first demonstration of pharmacological selectivity due to differences in receptor-membrane interactions at any GPCR. The possibility to achieve pharmacological selectivity based on receptor-membrane interactions changes our view on the molecular basis of pharmacological selectivity and opens new ways for the development of a novel pharmaceutics. Více

Publikace

Randáková; Alena - Nelic; Dominik - Ungerová; Dana - Nwokoye; P. - Su; Q. - Doležal; Vladimír - El-Fakahany; E. E. - Boulos; J. - Jakubík; Jan . Novel M-2-selective; G(i)-biased agonists of muscarinic acetylcholine receptors . British Journal of Pharmacology. 2020; 177(9); 2073-2089 . IF = 7.730 [ASEP] [ doi ]
Randáková; Alena - Nelic; Dominik - Doležal; Vladimír - El-Fakahany; E. E. - Boulos; J. - Jakubík; Jan . Agonist-Specific Conformations of the M-2 Muscarinic Acetylcholine Receptor Assessed by Molecular Dynamics . Journal of Chemical Information and Modeling. 2020; 60(4); 2325-2338 . IF = 4.549 [ASEP] [ doi ]
Jakubík; Jan - Randáková; Alena - Chetverikov; Nikolai - El-Fakahany; E. E. - Doležal; Vladimír . The operational model of allosteric modulation of pharmacological agonism . Scientific Reports. 2020; 10(1)); 14421 . IF = 3.998 [ASEP] [ doi ]
Jakubík; Jan - El-Fakahany; E. E. Current Advances in Allosteric Modulation of Muscarinic Receptors . Biomolecules. 2020; 10(2)); 325 . IF = 4.082 [ASEP] [ doi ]
Jakubík, Jan - Randáková, Alena - Rudajev, Vladimír - Zimčík, Pavel - El-Fakahany, E. E. - Doležal, Vladimír . Applications and limitations of fitting of the operational model to determine relative efficacies of agonists . Scientific Reports 2019, 9(Mar 15)), 4637 . IF = 3.998 [ASEP] [ doi ]
Jakubík, Jan - Randáková, Alena - El-Fakahany, E. E. - Doležal, Vladimír . Analysis of equilibrium binding of an orthosteric tracer and two allosteric modulators . PLoS ONE 2019, 14(3)), e0214255 . IF = 2.740 [ASEP] [ doi ]
Randáková, Alena - Rudajev, Vladimír - Doležal, Vladimír - Boulos, J. - Jakubík, Jan . Novel long‐acting antagonists of muscarinic ACh receptors . British Journal of Pharmacology 2018, roč. 175, 10, p. 1731-1743 . IF = 6.583 [ASEP] [ doi ]
Randáková, Alena - Dolejší, Eva - Rudajev, Vladimír - Zimčík, Pavel - Doležal, Vladimír - El-Fakahany, E. E. - Jakubík, Jan . Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline . Neuropharmacology 2018, roč. 133, May 1, p. 129-144 . IF = 4.367 [ASEP] [ doi ]
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 . Chemical Biology & Drug Design 2018, roč. 91, 1, p. 93-104 . IF = 2.256 [ASEP] [ doi ]
Jakubík, Jan - Randáková, Alena - Zimčík, Pavel - El-Fakahany, E. E. - Doležal, Vladimír . Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors . Scientific Reports. 2017, roč. 7, Jan 16, článku 40381 . IF = 4.122 [ASEP] [ doi ]
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 . Scientific Reports. 2016, roč. 6, Aug 3, p. 30698 . IF = 4.259 [ASEP] [ doi ]
Dolejší, Eva - Liraz, O. - Rudajev, Vladimír - Zimčík, Pavel - Doležal, Vladimír - Michaelson, D. M. Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice . Journal of Neurochemistry. 2016, roč. 136, 3, p. 503-509 . IF = 4.083 [ASEP] [ doi ]
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 . Frontiers in Aging Neuroscience. 2016, roč. 8, Mar 16, p. 41 . IF = 4.504 [ASEP] [ doi ]
Randáková, Alena - Dolejší, Eva - Rudajev, Vladimír - Zimčík, Pavel - Doležal, Vladimír - El-Fakahany, E. E. - Jakubík, Jan . Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms . Pharmacological Research. 2015, Vol. 97, Jul 2015, p. 27-39 . IF = 4.816 [ASEP] [ doi ]
Michal, Pavel - El-Fakahany, E. E. - Doležal, Vladimír . Changes in Membrane Cholesterol Differentially Influence Preferential and Non-preferential Signaling of the M1 and M3 Muscarinic Acetylcholine Receptors . Neurochemical Research. 2015, Vol. 40, 10, p. 2068-2070 . IF = 2.472 [ASEP] [ doi ]
Jakubík, Jan - El-Fakahany, E. E. - Doležal, Vladimír . Towards predictive docking at aminergic G-protein coupled receptors . Journal of Molecular Modeling. 2015, Vol. 21, 11, p. 284 . IF = 1.438 [ASEP] [ doi ]
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 . Journal of Biological Chemistry. 2015, Vol. 290, 39, p. 23616-23630 . IF = 4.258 [ASEP] [ doi ]
Janíčková, Helena - Rudajev, Vladimír - Dolejší, Eva - Koivisto, H. - Jakubík, Jan - Tanila, H. - El-Fakahany, E. E. - Doležal, Vladimír . Lipid-Based Diets Improve Muscarinic Neurotransmission in the Hippocampus of Transgenic APPswe/PS1dE9 Mice . Current Alzheimer Research. 2015, Vol. 12, 10, p. 923-931 . IF = 3.145 [ASEP] [ doi ]
Šantrůčková, Eva - Doležal, Vladimír - El-Fakahany, E. E. - Jakubík, Jan . Long-Term Activation upon Brief Exposure to Xanomleline Is Unique to M1 and M4 Subtypes of Muscarinic Acetylcholine Receptors . PLoS ONE 2014, roč. 9, 2, e88910. ISSN 1932-6203. IF = 3.234 [ASEP] [ doi ]
Jakubík, Jan - Zimčík, Pavel - Randáková, Alena - Fuksová, Květoslava - El-Fakahany, E. E. - Doležal, Vladimír . Molecular Mechanisms of Methoctramine Binding and Selectivity at Muscarinic Acetylcholine Receptors . Molecular Pharmacology 2014, roč. 86, 2, p. 180-192. ISSN 0026-895X. IF = 4.128 [ASEP] [ doi ]
Jakubík, Jan - Šantrůčková, Eva - Randáková, Alena - Janíčková, Helena - Zimčík, Pavel - Rudajev, Vladimír - Michal, Pavel - El-Fakahany, E. E. - Doležal, Vladimír . Outline of therapeutic interventions with muscarinic receptor-mediated transmission . Physiological Research 2014, roč. 63, suppl.1, s177-s189. ISSN 0862-8408. IF = 1.293 [ASEP]
Janíčková, Helena - Rudajev, Vladimír - Zimčík, Pavel - Jakubík, Jan - Tanila, H. - El-Fakahany, E. E. - Doležal, Vladimír . Uncoupling of M1 muscarinic receptor/G-protein interaction by amyloid beta(1-42) . Neuropharmacology, 2013, Vol. 67, April, p. 272-283 . IF = 4.114 [ASEP] [ doi ]
Jakubík, Jan - Randáková, Alena - Doležal, Vladimír . On homology modeling of the M-2 muscarinic acetylcholine receptor subtype . Journal of Computer-Aided Molecular Design, 2013, Vol. 27, 6, p. 525-538 . IF = 3.172 [ASEP] [ doi ]
Boulos, J. - Jakubík, Jan - Randáková, Alena - Avila, C. Synthesis of N-Substituted Piperidine Salts as Potential Muscarinic Ligands for Alzheimer's Applications . Journal of Heterocyclic Chemistry, 2013, Vol. 50, 6, p. 1363-1367 . IF = 1.224 [ASEP] [ doi ]
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 . Journal of Neurochemistry, 2012, Vol. 120, 4, p. 631-640 . IF = 3.973 [ASEP] [ doi ]
Kučerová, Lucie - Brož, Václav - Fleischmannová, Jana - Šantrůčková, Eva - Sidorov, Roman - Doležal, Vladimír - Žurovec, Michal . Characterization of the Drosophila adenosine receptor: the effect of adenosine analogs on cAMP signaling in Drosophila cells and their utility for in vivo experiments . Journal of Neurochemistry, 2012, Vol. 121, 3, p. 383-395 . IF = 3.973 [ASEP] [ doi ]
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 . NMR Structure and Action on Nicotinic Acetylcholine Receptors of Water-soluble Domain of Human LYNX1 . Journal of Biological Chemistry, 2011, Vol. 286, 12, p. 10618-10627 . IF = 4.773 [ASEP] [ doi ]
Jakubík, Jan - Janíčková, Helena - Randáková, Alena - El-Fakahany, E. E. - Doležal, Vladimír . Subtype Differences in Pre-Coupling of Muscarinic Acetylcholine Receptors . PLoS ONE, 2011, Vol. 6, 11, e27732 . IF = 4.092 [ASEP] [ doi ]
Jakubík, Jan - Janíčková, Helena - El-Fakahany, E. E. - Doležal, Vladimír . Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy . British Journal of Pharmacology, 2011, Vol. 162, 5, p. 1029-1044 . IF = 4.409 [ASEP] [ doi ]
Machová, Eva - Rudajev, Vladimír - Smyčková, Helena - Koivisto, H. - Tanila, H. - Doležal, Vladimír . Functional cholinergic damage develops with amyloid accumulation in young adult APPswe/PS1dE9 transgenic mice . Neurobiology of Disease, 2010, Vol. 38, 1, p. 27-35 . IF = 5.121 [ASEP] [ doi ]
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 . PLoS ONE, 2010, Vol. 5, 12, e15722-16 . IF = 4.411 [ASEP] [ doi ]
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 . FEBS Journal, 2009, Vol. 276, 18, p. 5065-5075 . IF = 3.042 [ASEP] [ doi ]
Michal, Pavel - Rudajev, Vladimír - El-Fakahany, E. E. - Doležal, Vladimír . Membrane cholesterol content influences binding properties of muscarinic M2 receptors and differentially impacts activation of second messenger pathways . European Journal of Pharmacology, 2009, Vol. 606, 1-3, p. 50-60 . IF = 2.585 [ASEP] [ doi ]
Machová, Eva - O´Regan, S. - Newcombe, J. - Meunier, F. M. - Prentice, J. - Dove, R. - Lisá, Věra - Doležal, Vladimír . Detection of choline transporter-like 1 protein CTL1 in neuroblastoma × glioma cells and in the CNS, and its role in choline uptake . Journal of Neurochemistry, 2009, Vol. 110, 4, p. 1297-1309 . IF = 3.999 [ASEP] [ doi ]
Bouřová, Lenka - Stöhr, Jiří - Lisý, Václav - Rudajev, Vladimír - Novotný, Jiří - Svoboda, Petr . G-protein activity in Percoll-purified plasma membranes, bulk plasma membranes, and low-density plasma membranes isolated from rat cerebral cortex . Medical Science Monitor, 2009, Vol. 15, 4, BR111-BR122 . IF = 1.543 [ASEP]
Machová, Eva - Jakubík, Jan - Michal, Pavel - Oksman, M. - Iivonen, H. - Tanila, H. - Doležal, Vladimír . Impairment of muscarinic transmission in transgenic APPswe/PS1dE9 mice . Neurobiology of Aging, 2008, Vol. 29, 3, p. 368-378 . IF = 5.959 [ASEP] [ doi ]
Drastichová, Zdeňka - Bouřová, Lenka - Lisý, Václav - Hejnová, L. - Rudajev, Vladimír - Stöhr, Jiří - Durchánková, Dana - Ostašov, Pavel - Teisinger, Jan - Soukup, Tomáš - Novotný, Jiří - Svoboda, Petr . Subcellular redistribution of trimeric G-proteins – potential mechanism of desensitization of hormone response: internalisation, solubilization, down-regulation . Physiological Research, 2008, Vol. 57, Suppl.3, S1-S10 . IF = 1.653 [ASEP]
Michal, Pavel - El-Fakahany, E. E. - Doležal, Vladimír . Muscarinic M2 receptors directly activate Gq/11 and Gs G-proteins . Journal of Pharmacology and Experimental Therapeutics, 2007, Vol. 320, 2, p. 607-614 . IF = 4.003 [ASEP]
Machová, Eva - Jakubík, Jan - El-Fakahany, E. E. - Doležal, Vladimír . Wash-Resistantly Bound Xanomeline Inhibits Acetylcholine Release by Persistent Activation of Presynaptic M2 and M4 Muscarinic Receptors in Rat Brain . Journal of Pharmacology and Experimental Therapeutics, 2007, Vol. 322, 1, p. 316-323 . IF = 4.003 [ASEP]

Fotogalerie oddělení

Celá fotogalerie

Lidé

Mgr. Jan Jakubík, PhD
vedoucí oddělení
MUDr. Vladimír Doležal, DrSc.
zástupce vedoucího oddělení
MUDr. et Mgr. Helena Janíčková, PhD
vědecká pracovnice
Mgr. Eva Dolejší, PhD
vědecká asistentka
Mgr. Alena Randáková, PhD
vědecká asistentka
Alice Abbondanza, MSc
postgraduální studentka

Nikolai Chetverikov, MSc

postgraduální student

Denise Greco, MSc

odborná pracovnice VaV

Bc. Jana Bláhová
studentka
Trisha Dhabalia
studentka

Bc. Mutale Jane Mulenga

studentka

Bc. Dominik Nelic

student

Bc. Alexandra Tyshkevich
studentka
Dana Ungerová
technická pracovnice
 

Bc. Jan Eliáš

externí odborný pracovník VaV