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Molecular mechanisms engaged in the development of drug addiction
Pallag, Gergely ; Novotný, Jiří (advisor) ; Nerandžič, Vladimír (referee)
Drug use is part of the human life from the ancient times. Besides their recreational utilization, sustained misuse of these substances can lead to the development of drug addiction especially in susceptible individuals and thus cause serious health and social problems. The aim of this thesis is to briefly introduce brain structures which are affected by addictive substances, and describe some of the mechanisms and molecules that contribute to addiction. A crucial brain structure which plays a role in drug addiction is the reward system, with dopamine as the main neurotransmitter. After repeated use of drugs, in neurons of this system certain molecules and epigenetic changes are accumulating that promote chronic nature of addiction. Especially important is the highly stable transcription factor ΔFosB, which in cooperation with other molecules promotes relapse even after several months or years of the last drug use. Powered by TCPDF (www.tcpdf.org)
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Classification, structure and function of α-adrenergic receptors.
Makarova, Anna-Marie ; Hejnová, Lucie (advisor) ; Rudajev, Vladimír (referee)
Adrenergic receptors are ones of the most investigated receptors today. Signal transduction by adrenergic receptors is involved in stress response. Stress activates the sympathicus and the hypothalamic-pituitary-adrenal axis of autonomic nervous system. Understanding effects of this activation on adrenergic signalisation is important for affection of the "fight of flight" reaction. Affecting the activity of sympathetic nerve sis important subject of interest in pharmacology and many drugs are developed using this actions. This thesis deals with a group α-adrenergic receptors and its subtypes. One part is devoted to structure which is subject of many explorations recently especially. Next chapter focuses on signal transduction mediated by α-adrenergic receptors. The last section refers to multitude of physiologic functions induced by these receptors. Powered by TCPDF (www.tcpdf.org)
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Postnatal development of GABAb-receptors in the frontal rat brain cortex
Kagan, Dmytro ; Svoboda, Petr (advisor) ; Langmeier, Miloš (referee) ; Mareš, Pavel (referee)
In this work, the detailed analysis of GABAB-R/G protein coupling in the course of pre- and postnatal development of rat brain cortex indicated the significant intrinsic efficacy of GABAB-receptors already shortly after the birth: at postnatal day 1 and 2. Subsequently, both baclofen and SKF97541-stimulated G protein activity, measured as the high-affinity [35 S]GTPγS binding, was increased. The highest level of agonist-stimulated [35 S]GTPγS binding was detected at postnatal days 14 and 15. In older rats, the efficacy, i.e. the maximum response of baclofen- and SKF97541-stimulated [35 S]GTPγS binding was continuously decreased so, that the level in adult, 90-days old rats was not different from that in newborn animals. The potency of G protein response to baclofen stimulation, characterized by EC50 values, was also high at birth but unchanged by further development. The individual variance among the agonists was observed in this respect, as the potency of SKF97541 response was decreased when compared in 2-days old and adult rats. The highest plasma membrane density of GABAB-R, determined by saturation binding assay with specific antagonist [3 H]CGP54626AA, was observed in 1-day old animals. The further development was reflected in decrease of receptor number. The adult level was ≈3- fold lower than...
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Muscarinic acetylcholine transmission and Alzheimer's disease
Janíčková, Helena ; Doležal, Vladimír (advisor) ; Blahoš, Jaroslav (referee) ; Rokyta, Richard (referee)
Impairment of the cholinergic neurotransmission system is regularly detected in animal models of Alzheimer's disease as well as in human patients suffering from this serious disease. Moreover, there is increasing amount of evidence suggesting that activation of individual mAChR subtypes specifically influences the cleavage of APP, the precursor for β-amyloid. APP can be processed in an amyloidogenic or non-amyloidogenic pathway and a relative abundance of these patways contributes to establishing the final concentration of neurotoxic β-amyloid in the brain. In this work, I have studied the acute and chronic effects of A β1-42 on binding and functional characteristics of mAChR. I have demonstrated that Aβ1-42 present in cell culture expressing the individual subtypes of mAChR negatively and specifically influences the function of the M1 mAChR subtype. I have also detected a decline in muscarinic receptor-mediated signal transduction in brain tissue of young adult APPswe/PS1dE9 mice, a commonly used animal model of Alzheimer's disease. Demonstration of the impairment of muscarinic transmissin in transgenic mice by soluble β-amyloid that occurs earlier than amyloid pathology and behavioral deficit, and its imitation by soluble Aβ1-42 in vitro lend strong support to the notion of the early involvement...
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Evolution of olfactory receptors
Klempt, Petr ; Stopka, Pavel (advisor) ; Vinkler, Michal (referee)
This bachelor thesis deals with the largest gene family of mammals which encode olfactory receptors. Olfactory receptors fall in rhodopsin-like GPCRs subfamily, approximately 600 - 800 millions of years old. At least from this time, olfactory receptors play, as a part of one of the oldest senses (smell), fundamental role in detection of chemical cues from water or air. This work summarizes large repertoire of olfactory receptors and its changes during the evolution of important animal taxons with emphasis on number and fraction of functional and nonfunctional olfactory receptor genes. Those values are part of criteria used for olfactory ability of animals. Olfactory receptors are typically placed on surface of sensory neuron placed in olfactory epithelium, where they bind various odorants and triggers signal cascade which leads to neuron's membrane depolarization. Therefore, about one half of this work summarizes knowledge of olfactory receptor's molecular biology like their structure, main parts of signal cascade (Gαolf, ACIII, CNG channel, Ca2+ dependent Cl- channel) just as parts needed for steady-state establishment. Expression of olfactory receptors detected in amount of non-olfactory tissues (mussels, sperm, brain etc.), indicate possibly important biomedical roles of this receptors.
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Role of metabotropic glutamate receptors and their associated proteins in physiology and pathophysiology
Kumpošt, Jiří ; Blahoš, Jaroslav (advisor) ; Dráber, Petr (referee) ; Viklický, Vladimír (referee)
of the thesis Glutamate is a main excitatory neurotransmitter in the brain of mammals, which activates both ionotropic and metabotropic glutamate receptors. Ionotropic receptors are responsible for fast synaptic transmission leading to membrane depolarization and Ca2+ influx into the cell. On the other hand mGlu receptors play an important role in regulation of the transmission via heterotrimeric G-proteins and activation of various signaling pathways. Postsynaptically localized group I mGlu receptors (mGluR1, 5) together with ionotropic NMDA and AMPA receptors share common large receptor signaling complexes, or signalosome facilitating glutamate signal transductions. Individual mGluR1 splice variants are differently associated with signalosome including scaffold proteins like PSD-95 which organize postsynaptic density (PSD). Heterodimerization of different mGluR1 splice variants is a focal point of my thesis together with investigation of recently discovered protein IL1RAPL1 (interleukin-1 receptor accessory protein-like 1) and its role in organization of postsynaptic signalosome. Using biochemical, immunocytochemical and functional assays we showed heterodimers of mGluR1a/1b were expressed on the plasma membrane and that heterodimers are fully functional in the recombinant system. Next we showed...
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Molecular dynamics simulations of biomolecules
Naništa, Ján ; Barvík, Ivan (advisor) ; Bok, Jiří (referee)
This study deals with classical molecular dynamics simulations of time evolution of a biomolecular system. The simulated system consists of the D3 GPCR membrane receptor for dopamine surrounded by a cell membrane and covered with water molecules and ions. The aim was to analyze the ability of Eticlopride to bind into the active site of the GPCR receptor.
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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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