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Research Overview

Research Overview Graphic
The laboratory is part of the Department of Biochemistry at the University of Nicolas Copernicus in Torun, Poland. We focus on studying the molecular mechanisms involving pentameric ligand-gated ion channel (pLGIC) function and regulation. The pLGIC family, in mammals, comprises excitatory: nicotinic acetylcholine receptors (nAChRs), serotonin type 3 receptors (5-HT3Rs), and zinc-activated ion channels; and inhibitory: γ-aminobutyric acid type A receptors (GABAARs) and glycine receptors (GlyRs). The pLGIC family relays the chemical-to-electrical signaling transduction of neurons. Binding of released synaptic neurotransmitters stabilizes the opening of an intrinsic channel passively conducting ions across the membrane, which thereby triggers cell depolarization or hyperpolarization. As they are ubiquitously expressed in virtually all neurons, pLGICs contribute to all major central nervous system functions; including: sensory and motor processing, central autonomous control, memory and attention, sleep and wakefulness, reward, pain, anxiety, emotions, and cognition. Drug addiction, specifically smoking, and neurological disorders such as Alzheimer’s disease, schizophrenia, and Parkinson’s disease have long been linked to the cholinergic system, specifically nAChRs. Unfortunately, the many years of pharmacological study have not yielded robust therapies for the maledictions caused by a dysfunction of nAChRs which beset individuals. And so, by employing many facets of biochemical techniques, from molecular biology, protein biochemistry, electrophysiology, immunofluorescence, and pharmacology, our goal is to gleam information about the intracellular domain and thus the regulation/trafficking of these receptors. Targeting their regulatory proteins may combat neurodegenerative disorders better than targeting the receptors themselves.

Team Members

We are always looking for motivated individuals interested in our research. If you feel you are qualified do not hesitate to contact us.

To contact any current member simply click on their image.
Dr. Ákos Nemecz

adiunkt


Dr. Ákos Nemecz
dr Dorota Nemecz

adiunkt


dr Dorota Nemecz
Onyx

Lab Mascot/Guardian


Onyx

Postdoctoral Scholars

Doctoral Students

Zainab Kazim

Academia Copernicana
Interdisciplinary Doctoral School


Zainab Kazim
Weronika Nowak

Academia Copernicana
Interdisciplinary Doctoral School


Weronika Nowak

Master's Students

Katarzyna Świstowska

Biotechnology


Katarzyna Świstowska
Zuzanna Szutkowska

Biotechnology


Zuzanna Szutkowska
Kamila Grygiel

Biotechnology


Kamila Grygiel
Marcelina Mikołajczyk

Biotechnology


Marcelina Mikołajczyk
Magda Tylenda

Biotechnology


Magda Tylenda
Kuba Wolinski

Biotechnology


Kuba Wolinski

Bachelor Students

Former Members

Agata Wikarska

Bachelor Students


Agata
Wikarska
Kacper Roszak

Bachelor Students


Kacper
Roszak
Jakub Lewandowski

Bachelor Students


Jakub
Lewandowski

Projects

Combating addiction by targeting α3β4*-nicotinic acetylcholine receptors
OPUS21-2021/41/B/NZ7/03101

According to the World Health Organization tobacco use kills more than 7 million people every year and costs an estimate of US1.4 trillion in global economic burden resulting from loss of productivity and healthcare costs. Smoking addiction has long been linked to the cholinergic system, specifically nicotinic acetylcholine receptors, through the principal addictive component in cigarettes: nicotine. These receptors bind a chemical signal (neurotransmitters) and convert it to an electrical signal (ion conductance). They belong to a class of ligand-gated ion channels composed of five individual similar or sometimes identical protein subunits that form an ion channel, otherwise known as pentameric ligand-gated ion channels. This family of receptors is involved in all major functions of the central nervous system. Numerous years of pharmacological and therapeutic research targeting the neurotransmitter and modulatory binding sites of nicotinic acetylcholine receptors has not yet produced any robust anti-addiction therapies. Recent genomic studies have identified a specific gene cluster and therefore the α3-, β4-, α5-subunits of the nicotinic acetylcholine receptor family which are correlated to smoking addiction. An inhibition of this assembly of nicotinic receptor subunits has been shown to reduce the reward effect caused by drug interactions in the brain, and thereby attenuate nicotine as well as other drug addictions.
This project expressly aims to synthetically generate and isolate selective single-domain antibodies which act as inhibitory modulators of α3-β4 nicotinic acetylcholine receptor subunits. These small versatile antibodies are derived from camelids such as llamas, alpacas, camels, and dromedaries. Very recently it has been possible to create synthetic libraries of single-domain antibodies and thereby avoid the use of camelids to generate them. These synthetically generated and selective nanobodies will also be used as tools to properly localize various α3β4 receptor assemblies in the brain, thereby better understanding the role of they play in the brain’s reward pathway.
Understanding the role nicotinic acetylcholine receptors play in addiction is an important aspect to developing efficient therapeutics. This proposal attempts to develop therapeutics to help alleviate the drug dependence of smoking and other drug addictions, thereby reducing the economic burden that cancer and other addiction-related diseases have on the healthcare system. The use of single-domain antibodies as tools to study receptor localization will also elaborate upon the current understanding of the addiction/reward pathway in the brain.

Past Projects

Investigation into the mechanism of regulation of nicotinic acetylcholine receptors
POLS-2020/37/K/NZ3/04098

Neurological disorders such as Alzheimer’s disease, schizophrenia, and Parkinson’s disease, in addition to drug addiction have long been linked to the cholinergic system, and specifically nicotinic acetylcholine receptors. These receptors bind a chemical signal (neurotransmitters) and convert it to an electrical signal (ion conductance). They belong to a class of pentameric ligand-gated ion channels composed of five individual similar or sometimes identical protein subunits that form an ion channel. They have a conserved general structure which includes three domains. The extracellular domain, the protein region located outside of the cell, contains the neurotransmitter binding site. The transmembrane domain forms the ion channel pore that selectively allows ions to flow along their concentration gradient. The intracellular domain, the protein region inside of the cell, is thought to be primarily involved in the regulation and trafficking of the receptor. This family of receptors is involved in all major functions of the central nervous system. An enhanced understanding of the mechanisms for functional modulation, in addition to the structural determination of the neurotransmitter binding site, resulted in many pharmacological advances. Yet the numerous years of research have not produced any robust therapies for the maledictions caused by a dysfunction of nicotinic acetylcholine receptors.
This project expressly aims to study the mechanism(s) of functional regulation of nicotinic acetylcholine receptors through their intracellular domain, for which very little is known. Targeting the regulatory system of these receptors may form the basis for developing new therapeutics against neurological disorders.
Within the project a protein composed of an intracellular domain of nicotinic acetylcholine receptors linked to a soluble homologous protein will be created. Using this soluble linked-protein as a tool to identify proteins which interact with the intracellular domain, this project will determine novel targets for current pharmaceutical therapeutic objectives. These newly discovered targets will generate more successful remedies for neurological disorders such as Alzheimer’s and schizophrenia.
Additionally this project will study the mechanisms of action of the identified regulatory proteins. The subtype selective regulation may be identified by studying the role that the various subunit compositions of the receptor, otherwise known as stoichiometry, play in regulatory protein binding. Understanding the intricate mechanism of receptor regulation is important to combat neurodegenerative diseases. Through the development of small single-domain antibodies, nanobodies, against specific receptor stoichiometries this project will answer questions about regulatory differences and develop an understanding of regulatory mechanisms. These same nanobodies will also be used in the future projects as tools to properly localize given stoichiometries in the brain, creating a translational bridge between the biochemical mechanisms of regulation to the neurobiological system composition.
Understanding the mechanisms of regulation of nicotinic acetylcholine receptors, an aspect that has thus far remained elusive, is the key to developing efficient therapeutics for neurological disorders. This proposal attempts to develop such an understanding in the hope that a more effective forthcoming pharmaceutical approach may arise as a result.

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