1. Neurochemistry Group
We study physiology, biochemistry and pharmacology of cholinergic neurons at the molecular level and molecular pharmacology of other GPCRs. 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 the 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 receptors with G-proteins
- modelling of muscarinic receptor signal transduction.
2. Group of Biochemistry of Membrane Receptors
The research focuses on the cellular and molecular mechanisms of desensitization of hormone response mediated by the activation of G protein-coupled receptors (GPCR). G protein-coupled receptors are plasma membrane integral proteins that serve as transducers of extracellular signals across the plasma membrane bilayer to the cell interior. GPCR play a key role in the regulation of many physiological processes and functions. Moreover, GPCRs represent one of the most important groups of targets for therapeutics. The main areas of the research are:
- role of the cell membrane and membrane domains
- opioid receptors and drug addiction
- effect of monovalent ions on δ-opioid receptors – analysis of lithium effect in living cells and isolated cell membranes.
Publication 2015 - 2021
Projects
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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A biased agonist is a ligand which stabilizes a particular active conformation of a receptor, thus stimulating some responses but not others. Biased agonists might represent a novel and uniquely effective type of therapeutic agent with reduced side-effects.
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The aim of the project is to determine how disruption of cholinergic activation of striatal GABAergic interneurons alters striatal signalling and striatum-based behaviour by using a mouse model with deletion of the β2 nicotinic acetylcholine receptor subunit in striatal GABAergic interneurons.
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Cholesterol has been found to co-crystallize with a number of GPCRs. Our current experiments show that membrane cholesterol specifically binds to a muscarinic receptor and slows down their activation.
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Addiction to opioid drugs (opioids) represents one of the most severe forms of drug abuse. Opium is one of the oldest known drugs and is used for its medicinal and euphoric effects for thousands of years. Opioid dependence develops as a consequence of changes in the central nervous system (CNS) induced by prolonged exposure to opioid drugs, e.g., morphine, codein or heroin.
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Achievements
Proper determination of agonist efficacy is indispensable in the evaluation of agonist selectivity and bias to activation of specific signalling pathways. The operational model of pharmacological agonism is a useful means for achieving this goal.
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We have developed new muscarinic receptor agonists as a pharmacophore for the development of new non-addictive analgesics such as opiates or weakening of immunity as steroid analgesics. These muscarinic analgesics would not cause side effects such as incontinence, excessive salivation and sweating, and others.
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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.
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Proper determination of agonist efficacy is essential in the assessment of agonist selectivity and signalling bias. Agonist efficacy is a relative term that is dependent on the system in which it is measured, especially being dependent on receptor expression level. In this work, we analyse limits and pitfalls of fitting OM to experimental data.
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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.
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Publications
Ujčíková; Hana - Roubalová; Lenka - Lee; Y. S. - Slaninová; Jiřina - Brejchová; Jana - Svoboda; Petr
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The Dose-Dependent Effects of Multifunctional Enkephalin Analogs on the Protein Composition of Rat Spleen Lymphocytes; Cortex; and Hippocampus; Comparison with Changes Induced by Morphine
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Biomedicines. 2022; 10(8)); 1969
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IF = 4.757
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Ujčíková; Hana - Robles; D. - Yue; X. - Svoboda; Petr - Lee; Y. S. - Navratilova; E.
Time-Dependent Changes in Protein Composition of Medial Prefrontal Cortex in Rats with Neuropathic Pain
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International Journal of Molecular Sciences. 2022; 23(2)); 955
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IF = 6.208
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doi
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Ujčíková; Hana - Eckhardt; Adam - Hejnová; L. - Novotný; J. - Svoboda; Petr
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Alterations in the Proteome and Phosphoproteome Profiles of Rat Hippocampus after Six Months of Morphine Withdrawal: Comparison with the Forebrain Cortex
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Biomedicines. 2022; 10(1)); 80
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IF = 4.757
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Szczurowska; Ewa - Szánti-Pintér; Eszter - Randáková; Alena - Jakubík; Jan - Kudová; Eva
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Allosteric Modulation of Muscarinic Receptors by Cholesterol; Neurosteroids and Neuroactive Steroids
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International Journal of Molecular Sciences. 2022; 23(21)); 13075
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IF = 6.208
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Jůza; R. - Vojtěchová; I. - Štefková-Mazochová; K. - Dehaen; W. - Petrásek; T. - Prchal; L. - Kobrlová; T. - Janoušek; J. - Vlček; P. - Mezeiová; E. - Svozil; D. - Zdarová Karasová; J. - Pejchal; J. - Stark; H. - Satala; G. - Bojarski; A. J. - Kubacka; M. - Mogilski; S. - Randáková; Alena - Musílek; K. - Soukup; O. - Korábečný; J.
Novel D-2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment
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European Journal of Medicinal Chemistry. 2022; 232(Mar 15)); 114193
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IF = 7.088
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Jakubík; Jan - Randáková; Alena
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Insights into the operational model of agonism of receptor dimers
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Expert Opinion on Drug Discovery. 2022; 17(11); 1181-1191
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IF = 7.050
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Abbondanza; Alice - Bas; Irina Ribeiro - Modrák; Martin - Čapek; Martin - Minich; Jessica - Tyshkevich; Alexandra - Naser; Shahed - Rangotis; Revan - Houdek; Pavel - Sumová; Alena - Dumas; S. - Bernard; V. - Janíčková; Helena
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Nicotinic Acetylcholine Receptors Expressed by Striatal Interneurons Inhibit Striatal Activity and Control Striatal-Dependent Behaviors
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Journal of Neuroscience. 2022; 42(13); 2786-2803
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IF = 6.709
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doi
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Vošahlíková; Miroslava - Roubalová; Lenka - Brejchová; Jana - Alda; M. - Svoboda; Petr
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Therapeutic lithium alters polar head-group region of lipid bilayer and prevents lipid peroxidation in forebrain cortex of sleep-deprived rats
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Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids. 2021; 1866(9)); 158962
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IF = 5.288
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Ujčíková; Hana - Hejnová; L. - Eckhardt; Adam - Roubalová; Lenka - Novotný; J. - Svoboda; Petr
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Impact of three-month morphine withdrawal on rat brain cortex; hippocampus; striatum and cerebellum: proteomic and phosphoproteomic studies
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Neurochemistry International. 2021; 144(Mar)); 104975
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IF = 4.297
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Staszewski; M. - Nelic; Dominik - Jończyk; J. - Dubiel; M. - Frank; A. - Stark; H. - Bajda; M. - Jakubík; Jan - Walczyński; K.
Guanidine Derivatives: How Simple Structural Modification of Histamine H3R Antagonists Has Led to the Discovery of Potent Muscarinic M2R/M4R Antagonists
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ACS Chemical Neuroscience. 2021; 12(13); 2503-2519
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IF = 5.780
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doi
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Roubalová; Lenka - Vošahlíková; Miroslava - Slaninová; Jiřina - Kaufman; Jonáš - Alda; M. - Svoboda; Petr
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Tissue-specific protective properties of lithium: comparison of rat kidney; erythrocytes and brain
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Naunyn-Schmiedeberg's Archives of Pharmacology. 2021; 394(5); 955-965
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IF = 3.195
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doi
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Randáková; Alena - Nelic; Dominik - Hochmalová; Martina - Zimčík; Pavel - Mulenga; Mutale Jane - Boulos; J. - Jakubík; Jan
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Fusion with Promiscuous G alpha(16) Subunit Reveals Signaling Bias at Muscarinic Receptors
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International Journal of Molecular Sciences. 2021; 22(18)); 10089
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IF = 6.208
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doi
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Randáková; Alena - Jakubík; Jan
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Functionally selective and biased agonists of muscarinic receptors
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Pharmacological Research. 2021; 169(July)); 105641
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IF = 10.334
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doi
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Kljakic; O. - Al-Onaizi; M. - Janíčková; Helena - Chen; K. S. - Guzman; M. S. - Prado; M. A. M. - Prado; V. F.
Cholinergic transmission from the basal forebrain modulates social memory in male mice
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European Journal of Neuroscience. 2021; 54(6); 6075-6092
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IF = 3.698
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doi
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Jůza; R. - Štefková; K. - Dehaen; W. - Randáková; Alena - Petrásek; T. - Vojtěchová; I. - Kobrlová; T. - Pulkrábková; L. - Mucková; L. - Mecava; M. - Prchal; L. - Mezeiová; E. - Musílek; K. - Soukup; O. - Korábečný; J.
Synthesis and In Vitro Evaluation of Novel Dopamine Receptor D-2 3;4-dihydroquinolin-2(1H)-one Derivatives Related to Aripiprazole
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Biomolecules. 2021; 11(9)); 1262
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IF = 6.064
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doi
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Jakubík; Jan - El-Fakahany; E. E.
Allosteric Modulation of GPCRs of Class A by Cholesterol
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International Journal of Molecular Sciences. 2021; 22(4)); 1953
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IF = 6.208
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Holáň; Vladimír - Echalar; Barbora - Palacká; Kateřina - Kössl; Jan - Boháčová; Pavla - Krulová; Magdaléna - Brejchová; Jana - Svoboda; Petr - Zajícová; Alena
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The Altered Migration and Distribution of Systemically Administered Mesenchymal Stem Cells in Morphine-Treated Recipients
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Stem Cell Reviews and Reports. 2021; 17(4); 1420-1428
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IF = 6.692
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Dolejší; Eva - Szánti-Pintér; Eszter - Chetverikov; Nikolai - Nelic; Dominik - Randáková; Alena - Doležal; Vladimír - Kudová; Eva - Jakubík; Jan
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Neurosteroids and steroid hormones are allosteric modulators of muscarinic receptor
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Neuropharmacology. 2021; 199(Nov 1)); 108798
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IF = 5.273
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doi
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Dolejší; Eva - Chetverikov; Nikolai - Szánti-Pintér; Eszter - Nelic; Dominik - Randáková; Alena - Doležal; Vladimír - El-Fakahany; E. E. - Kudová; Eva - Jakubík; Jan
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Neuroactive steroids; WIN-compounds and cholesterol share a common binding site on muscarinic acetylcholine receptors
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Biochemical Pharmacology. 2021; 192(Oct)); 114699
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IF = 6.100
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doi
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Cechová; Kristína - Lan; Ch. - Macík; M. - Barthes; N. P. F. - Jung; M. - Ulbrich; M. H.
Kappa but not delta or mu opioid receptors form homodimers at low membrane densities
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Cellular and Molecular Life Sciences. 2021; 78(23); 7557-7568
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IF = 9.207
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2D electrophoretic map of plasma membrane proteins from the frontal cortex of rats
Effect of cholesterol depletion on thyroliberin receptor (TRH) distribution and morphology of HEK293 cells stably expressing the TRH-R-eGFP fusion protein (VTGP line)
NPY+ interneurons (green) in mouse striatum injected by AVV5-mCherry (red)
Neurons in mouse gzrus dentatus expressing GFP (green).
Department of Neurochemistry, July 2019
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).
