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Molecular physiology of adenosine receptors
Eichlerová, Lenka ; Novotný, Jiří (advisor) ; Hejnová, Lucie (referee)
Adenosine mediates its physiological signaling functions through the interaction with four receptor subtypes. The adenosine receptors belong to the superfamily of G protein-coupled receptors and are named A1, A2A, A2B and A3 receptors. Since they are widespread throughout the body, they are involved in many physiological processes and dysfunction of the adenosine system may have serious pathological consequences. Activity of adenosine receptors is inhibited by methylxanthines. Caffeine is a typical non-selective antagonist of the receptors, which is known to affect the sleep cycle. A great progress occurred in understanding the structure of adenosine receptors after the crystallographic model was solved for A2A receptor in complex with the antagonist ZM241385, which is referred to as super-caffeine. Understanding the receptor structure as well as the molecular mechanisms underlying the regulation of their function and interactions represent a starting point to the development of new drugs, which are going to be highly efficient and selective for each adenosine receptor subtype.
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The impact of positive inotropic and antiarrhythmic drugs on cardiovascular system
Kočková, Radka ; Linhart, Aleš (advisor) ; Janoušek, Jan (referee) ; Štengl, Milan (referee)
Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo A significant increase in cardiovascular medication use during pregnancy has occurred in recent years but only limited evidence on its safety profile is available. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. We tested metoprolol, carvedilol, or ivabradine for embryotoxicity and their acute effect on chick embryonic model. We used video microscopy and ultrasound biomicroscopy. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared to controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, 53%, respectively (controls 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of -adrenergic receptors showed a downward tendency during embryonic development but a negative chronotropic effect of tested drugs was increasingly pronounced with embryonic maturity. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death....
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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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The expression and regulation of Dexras1 in the rat brain under development
Kyclerová, Hana ; Bendová, Zdeňka (advisor) ; Jelínková, Dana (referee)
The Dexras1 gene was identified after induction by glucocorticoid dexamethasone in pituitary tumor cells. Dexras1 has also been found in other brain regions and in the peripheral organs but its expression is rhythmic only in the suprachiasmatic nuclei of the hypothalamus (SCN), where the mammalian main circadian pacemaker is located. Dexras1 expression was also affected by stress, amphetamine or prenatal alcohol exposure. Its role in cells has not yet been explained. Dexras1 GTPase activity has been determined to be dependent on the NMDA receptor stimulation. Dexras1 acts as an activator of G protein signaling in cells. Its role has been detected in neuronal iron homeostasis or in the regulation of main circadian pacemaker sensitivity to photic and nonphotic synchronization cues during the day. The aim of our study was to describe the Dexras1 mRNA expression in the rat brain during ontogeny and during development after visual sensory deprivation by in situ hybridization. The earliest Dexras1 expression was detected on embryonic day 20, in the rat SCN and the ventral posteromedial thalamic nucleus. Postnatally, its expression also appeared in other sensory areas, motor thalamic areas, hypothalamic areas involved in the regulation of water homeostasis, or in limbic system. Our results further show...
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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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The impact of positive inotropic and antiarrhythmic drugs on cardiovascular system
Kočková, Radka ; Linhart, Aleš (advisor) ; Janoušek, Jan (referee) ; Štengl, Milan (referee)
Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo A significant increase in cardiovascular medication use during pregnancy has occurred in recent years but only limited evidence on its safety profile is available. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. We tested metoprolol, carvedilol, or ivabradine for embryotoxicity and their acute effect on chick embryonic model. We used video microscopy and ultrasound biomicroscopy. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared to controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, 53%, respectively (controls 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of -adrenergic receptors showed a downward tendency during embryonic development but a negative chronotropic effect of tested drugs was increasingly pronounced with embryonic maturity. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death....
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Molecular physiology of adenosine receptors
Eichlerová, Lenka ; Novotný, Jiří (advisor) ; Hejnová, Lucie (referee)
Adenosine mediates its physiological signaling functions through the interaction with four receptor subtypes. The adenosine receptors belong to the superfamily of G protein-coupled receptors and are named A1, A2A, A2B and A3 receptors. Since they are widespread throughout the body, they are involved in many physiological processes and dysfunction of the adenosine system may have serious pathological consequences. Activity of adenosine receptors is inhibited by methylxanthines. Caffeine is a typical non-selective antagonist of the receptors, which is known to affect the sleep cycle. A great progress occurred in understanding the structure of adenosine receptors after the crystallographic model was solved for A2A receptor in complex with the antagonist ZM241385, which is referred to as super-caffeine. Understanding the receptor structure as well as the molecular mechanisms underlying the regulation of their function and interactions represent a starting point to the development of new drugs, which are going to be highly efficient and selective for each adenosine receptor subtype.
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