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The effect of long-term morphine and its withdrawal on selected signaling proteins in rat heart
Ilková, Karolina ; Novotný, Jiří (advisor) ; Černá, Věra (referee)
Morphine is considered the gold standard among analgesics in the treatment of severe pain due to its effects mediated by μ-opioid receptors. However, it also produces various side effects and poses a high risk of developing tolerance and dependence. The aim of this bachelor thesis is to contribute to the elucidation of the action of morphine at the molecular level in cardiac muscle. Changes of protein levels in key signaling molecules in the signaling cascade induced by morphine administration with increasing doses and subsequent abstinence for 24 hours, 1 month and 3 months were investigated. Specifically, these were adenosine A2b receptor, β2-adrenergic receptor, κ-opioid receptor, G protein subunits, GRK5 kinase, and β-arrestin 2. Data of changes in expression were obtained from cardiac tissue homogenates (left ventricle) by Western blot followed by immunodetection, captured on light-sensitive photofilms, and statistically evaluated by ANOVA. Morphine administration did not lead to statistically significant changes in G protein subunits, β- arrestin 2, GRK5 kinase, adenosine A2b receptor, β2-adrenergic receptor, or κ-opioid receptor in rat heart. Therefore in order to develop better and safer analgesics, there is a high necessity of understanding the underlying molecular mechanisms of morphine...
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Opioid receptors and their signaling system in the myocardium
Ladislav, Marek ; Novotný, Jiří (advisor) ; Neckář, Jan (referee)
The main objective of this bachelor thesis is to systematically collect and sort information about opioid receptors and their signaling system in the myocardium. Heart activity is controlled mainly by adrenergic signaling, and this work therefore contains also some data concerning the characteristic and significance of other relevant receptors. For better understanding, general basic information about opioid system, especially about the receptors and their signaling, is also provided. Relatively little is known about opioid receptors in the myocardium even though these receptors may have an important role especially in various pathophysiological conditions. There can be several reasons for this. The possibility of further characterization of opioid receptors in the myocardium is rather difficult due to the relatively small number of these receptors in heart tissue. The situation is somewhat complicated also by some differences in the modulation of cardiac function among different species. The complete molecular mechanism by which opioid receptors act on the myocardium has not yet been fully uncovered. Especially in the case of humans this knowledge can be crucial, because these receptors and their ligands could be used for medical purposes.
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Role of M4 muscarinic receptors in the central nervous system
Křížová, Monika ; Mysliveček, Jaromír (advisor) ; Slepička, Jakub (referee)
Muscarinic receptors type 4 are one of the five subtypes of muscarinic receptors, that are members of cholinergic receptors family, together with nicotinic receptors. An acetylcholine binding on the receptor triggers the receptor activation and the signal transmission into the cell by G-proteins located on plasmatic membrane, in the case of muscarinic receptors type 4 by Gi/o proteins. The M4 receptors are, just like other subtypes on muscarinic receptors, located in central and peripheral nervous system. In the central nervous system, they are mostly located in striatum and hippocampus. The M4 receptors have a whole range of regulative functions, the most significant one is most likely the regulation of a locomotion in striatum by the dopaminergic system. The muscarinic receptors type 4 are involved in many behavioural and cognitive processes and are therefore studied as potential drug target for the treatment of mental disorders. Key words: muscarinic receptors, M4 muscarinic receptors, GPCRs, cholinergic system, central nervous system
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Trimeric G protein-regulated signaling in neurodegenerative processes
Daňková, Karolína ; Novotný, Jiří (advisor) ; Weissová, Romana (referee)
Members of the large family of G proteins and their coupled receptors are involved in a variety of transduction processes the cell uses to respond to a received signal. Depending on their specific structure and function, they influence a wide range of effector molecules. A large body of research has shown that many neurodegenerative diseases have a negative impact on the signal pathways controlled by G proteins. Due to ageing population, neurodegenerative diseases are currently imposing a risk for growing numbers of people. The sequelae observed in the pathological development of such diseases include especially changes in membrane receptors representation or receptor uncoupling from G protein, which inhibits G subunits activation. The undesirable inhibition or over-stimulation of G proteins results in the increase or decrease in effector activity, which subsequently impacts the production of second messengers and the activity of subsequent members of the signal cascade. As a result, these alterations lead to an increase in intracellular concentration of Ca2+ ions, which then influence receptors responsible for excitotoxicity, and contribute to apoptosis and necrosis of neuronal population. The thesis summarizes the defects of signalling pathways controlled by trimeric G proteins in association...
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Role of M4 muscarinic receptors in the central nervous system
Křížová, Monika ; Mysliveček, Jaromír (advisor) ; Slepička, Jakub (referee)
Muscarinic receptors type 4 are one of the five subtypes of muscarinic receptors, that are members of cholinergic receptors family, together with nicotinic receptors. An acetylcholine binding on the receptor triggers the receptor activation and the signal transmission into the cell by G-proteins located on plasmatic membrane, in the case of muscarinic receptors type 4 by Gi/o proteins. The M4 receptors are, just like other subtypes on muscarinic receptors, located in central and peripheral nervous system. In the central nervous system, they are mostly located in striatum and hippocampus. The M4 receptors have a whole range of regulative functions, the most significant one is most likely the regulation of a locomotion in striatum by the dopaminergic system. The muscarinic receptors type 4 are involved in many behavioural and cognitive processes and are therefore studied as potential drug target for the treatment of mental disorders. Key words: muscarinic receptors, M4 muscarinic receptors, GPCRs, cholinergic system, central nervous system
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Lipid rafts and their role in transmembrane signaling mediated by G protein-coupled receptors
Ševčíková, Adéla ; Novotný, Jiří (advisor) ; Funda, Jiří (referee)
Membrane microdomains enriched in cholesterol and sphingolipids, known as lipid rafts and caveolae, contribute to many cellular processes including cholesterol homeostasis or lateral segregation of membrane proteins. This bachelor thesis describes the role of these membrane microdomains on transmembrane signaling mediated by G protein-coupled receptors. This is the most numerous and diverse family of receptors in mammalian cells that can affect a large number of physiological functions of the organism. A large amount of GPCR located in the membrane microdomains that concentrate specific signal components increase the variability of signaling. This issue is very complicated because the methods used to characterize these variable structures have limitations and each of the receptors exhibits specific behaviour. Key words: GPCRs, G proteins, lipid rafts, caveolae, transmembrane signaling
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The role of GPCRs and their signalling systems in cardioprotection
Svobodová, Ivana ; Novotný, Jiří (advisor) ; Holzerová, Kristýna (referee)
G protein-coupled receptors (GPCRs) are a family of membrane receptors with hundreds of members, many of them present in the heart, where their signalling systems are involved in regulation of many cellular processes. An important role of GPCRs is the cardioprotection against cardiac ischemia-reperfusion injury, which mainly involves the so-called RISK pathway containing of kinases signalling for cell survival and against apoptosis. By protecting the heart during ischemia/reperfusion they can prevent irreversible cardiac injury, including myocardial infarction or cardiac dysfunctions, which can lead to heart failure. GPCRs regulate many processes linked to pathophysiology of heart failure - hypertrophy, fibrosis, loss of cardiac function. Understanding the role of individual receptors in these cardioprotective and cardiotoxic processes is essential for the development of new drugs.
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Opioid receptors and their signaling system in the myocardium
Ladislav, Marek ; Novotný, Jiří (advisor) ; Neckář, Jan (referee)
The main objective of this bachelor thesis is to systematically collect and sort information about opioid receptors and their signaling system in the myocardium. Heart activity is controlled mainly by adrenergic signaling, and this work therefore contains also some data concerning the characteristic and significance of other relevant receptors. For better understanding, general basic information about opioid system, especially about the receptors and their signaling, is also provided. Relatively little is known about opioid receptors in the myocardium even though these receptors may have an important role especially in various pathophysiological conditions. There can be several reasons for this. The possibility of further characterization of opioid receptors in the myocardium is rather difficult due to the relatively small number of these receptors in heart tissue. The situation is somewhat complicated also by some differences in the modulation of cardiac function among different species. The complete molecular mechanism by which opioid receptors act on the myocardium has not yet been fully uncovered. Especially in the case of humans this knowledge can be crucial, because these receptors and their ligands could be used for medical purposes.
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