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INSTITUTE OF PHYSIOLOGY CAS

Cutting-edge science for health

Laboratory of Neurochemistry

Laboratory of Neurochemistry

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

Cholinergic modulation of striatum-based behaviour

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. More

Achievements

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. More

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. More

Publications

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 - 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 ]

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People

Mgr. Jan Jakubík, PhD
Head of the Laboratory
MUDr. Vladimír Doležal, DrSc.
Deputy Head of the Laboratory
MUDr. et Mgr. Helena Janíčková, PhD
Scientist
Mgr. Eva Dolejší, PhD
Junior Scientist
Mgr. Alena Randáková, PhD
Junior Scientist
Alice Abbondanza, MSc
Postgraduate Student

Nikolai Chetverikov, MSc

Postgraduate student

Denise Greco, MSc

Research Assistant

Bc. Jana Bláhová
Student
Trisha Dhabalia
Student

Bc. Mutale Jane Mulenga

Student

Bc. Dominik Nelic
Student
Bc. Alexandra Tyshkevich
Student
Dana Ungerová
Technician
 

Bc. Jan Eliáš

External Research Assistant