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Physiological functions of muscarinic receptor M3
Urbánková, Anna ; Randáková, Alena (advisor) ; Rudajev, Vladimír (referee)
Muscarinic receptors belong to the family of G-protein coupled receptors. G-proteins are heterotrimeric GTP-binding proteins that transfer signals from receptors to effectors. Effectors change levels of second messengers in the cell. Individual subtypes of muscarinic receptors bind to various classes of G-proteins. According to the G-protein coupling, muscarinic receptors change levels of various second messengers. Individual subtypes of the muscarinic receptor also differ in location and function. The M3 muscarinic receptor subtype is located primarily on the periphery where it mediates smooth muscle contraction and endocrine and exocrine secretion. The goal of this bachelor thesis was to describe the tissue-specific signalling pathways of the M3 receptor and their physiological roles in the periphery as well as in the central nervous system. Further, the role of M3 receptors in several pathologies is described. Finally, the M3 receptors as a possible pharmacological target will be discussed. Key words: muscarinic receptors M3, cell signaling, G-proteins
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Physiological functions of muscarinic receptor M3
Urbánková, Anna ; Randáková, Alena (advisor) ; Rudajev, Vladimír (referee)
Muscarinic receptors belong to the family of G-protein coupled receptors. G-proteins are heterotrimeric GTP-binding proteins that transfer signals from receptors to effectors. Effectors change levels of second messengers in the cell. Individual subtypes of muscarinic receptors bind to various classes of G-proteins.According to the G-protein coupling, muscarinic receptors change levels of various second messengers. Individual subtypes of the muscarinic receptor also differ in location and function. The M3 muscarinic receptor subtype is located primarily on the periphery where it mediates smooth muscle contraction and endocrine secretion. The goal of this bachelor thesis was to describe the tissue-specific signalling pathways of the M3 receptor and their physiological roles in the periphery as well as in the central nervous system. Further, the role of M3 receptors in several pathologies is described. Finally, the M3 receptors as a possible pharmacological target will be discussed. Key words: muscarinic receptors M3, cell signaling, G-proteins
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The role of cholesterol in the pathogenesis of Alzheimer's disease
Tax, Martin ; Rudajev, Vladimír (advisor) ; Randáková, Alena (referee)
Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia affecting a significant part of the aging population. It seems that the main cause of this disease is the accumulation of amyloid β (Aβ). Cholesterol is an important component of plasma membranes where it is essential for proper synapse function. Changes in its concentration are considered to be a risk factor for the onset and development of Alzheimer's disease. Data show that this lipid has an effect on Aβ synthesis and also has a role in Aβ cytotoxicity where it may promote the negative properties of Aβ or on the contrary can be protective against them.
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The role of cholinergic system in spatial cognition in rats
Klečáková, Kristýna ; Klement, Daniel (advisor) ; Randáková, Alena (referee)
The studies concentrated on spatial orientation are very popular in these days. Based on its results we can determine relations between cognitive behaviour and neural structures to find out principle of various deficits observed within neurodegenerative diseases (Alzheimer, Parkinson, schizophrenia,…), with usage of animal models. Large amount of experiments are focus on potential pharmacological substances that could revert damages of these diseases. Such experiments use special mazes where spatial tasks take place. Many different modifications of these arenas allow us to observe different types of used spatial orientation and associated processes (memory, attention, learning abilities...). Big progress for research of this field was also invention of microdialysis, that allow us to get information from extracellular brain space during task performance. Key words: cholinergic system, spatial orientation, cognitive map, place cells, nicotinic receptor, muscarinic receptor, Alzheimer's disease, baso-cortical pathways
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The role of oxidative stress in etiology of Alzheimer's disease
Šuláková, Anna ; Novotný, Jiří (advisor) ; Randáková, Alena (referee)
Oxidative stress is the result of an imbalance between the formation of reactive oxygen species and the ability of the body to detoxify these free radicals. As a result of this disbalance, harmful substances, especially peroxides and free radicals, accumulate in the body, resulting in damage of proteins, lipids and DNA leading to total cell destruction and necrosis. For this reason, oxidative stress contributes to the development of many serious diseases including atherosclerosis, many types of cancer, heart failure or neurodegenerative diseases such as Parkinson's disease, multiple sclerosis and Alzheimer's disease. Alzheimer's disease is a chronic neurodegenerative disease whose risk increases with age. It is an incurable disease affecting an ever increasing number of patient. Early AD symptoms include disorientation, loss of short-term memory, mood swings and problems with expression of thoughts. The causes of AD have not yet been fully clarified but there are speculations about importance of the role of tau-proteins and -amyloid plaques that form in AD progression. Oxidative stress can also play an important role, and may participate in the development of this disease. This work focuses mainly on the role of oxidative stress in pathophysiology and progression of AD. Key words:...
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The role of oxidative stress in etiology of Alzheimer's disease
Šuláková, Anna ; Novotný, Jiří (advisor) ; Randáková, Alena (referee)
Oxidative stress is the result of an imbalance between the formation of reactive oxygen species and the ability of the body to detoxify these free radicals. As a result of this disbalance, harmful substances, especially peroxides and free radicals, accumulate in the body, resulting in damage of proteins, lipids and DNA leading to total cell destruction and necrosis. For this reason, oxidative stress contributes to the development of many serious diseases including atherosclerosis, many types of cancer, heart failure or neurodegenerative diseases such as Parkinson's disease, multiple sclerosis and Alzheimer's disease. Alzheimer's disease is a chronic neurodegenerative disease whose risk increases with age. It is an incurable disease affecting an ever increasing number of patient. Early AD symptoms include disorientation, loss of short-term memory, mood swings and problems with expression of thoughts. The causes of AD have not yet been fully clarified but there are speculations about importance of the role of tau-proteins and -amyloid plaques that form in AD progression. Oxidative stress can also play an important role, and may participate in the development of this disease. This work focuses mainly on the role of oxidative stress in pathophysiology and progression of AD. Key words:...
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Activation mechanisms of muscarinic M1 receptor by atypical agonists
Randáková, Alena ; Doležal, Vladimír (advisor) ; Mysliveček, Jaromír (referee) ; Krůšek, Jan (referee)
Atypical agonists of muscarinic receptors bind to individual receptor subtypes with comparable affinity but activate them selectively to a certain extent. Molecular mechanism underlying this "functional selectivity" is not known and its elucidation may contribute to development of new atypical functionally selective agonists suitable for therapeutic use. Functional selectivity of atypical muscarinic agonists may be caused by a distinct molecular mechanism(s) of how these compounds activate the receptor. Agonist-specific conformations induced by structurally complex atypical agonists may lead to utilization of a parallel activation mechanism that is different than the activation mechanism induced by non-selective classical agonists. In order to examine this possibility we investigated whether the M1 receptor preferring atypical agonists xanomeline and N-desmethylclozapine, and the classical orthosteric agonists carbachol and oxotremorine, activate the M1 receptor through a common cascade of transmission switches. To this end we mutated key amino acids of the M1 receptor that are essential for ligand binding to the orthosteric binding site (D1053.32 , D993.26 ), receptor activation (transmission switch, D712.50 ), or interaction with G-protein (ionic lock switch, R1233.50 D1223.49 ). We compared...
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