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A study of the modulation of recombinant and native NMDA receptors by physical and chemical factors
Cais, Ondřej ; Vyklický, Ladislav (advisor) ; Blahoš, Jaroslav (referee) ; Chvátal, Alexandr (referee) ; Šťastný, František (referee)
Excitatory synaptic transmission in mammalian CNS is mostly mediated by ionotropic glutamate receptors. NMDA receptors, one of three subclasses of this ligand-activated ion channels family, are involved in memory formation and learning and also play a role in the pathogenesis of various neurodegenerative diseases. Current knowledge about NMDA receptors function is predominantly based upon results of in vitro experiments conducted at room temperature, far from physiological. The aim of this PhD thesis was to describe the temperature dependence of NMDA receptors. We determined the rate constants that characterise each step in the mechanism of recombinant NR1/NR2B receptors activation in the temperature range 25-45řC. The receptor desensitization, resensitization and glutamate unbinding turned out to be the most temperature sensitive of these processes. In addition to that, we described the temperature dependence of deactivation kinetics in various experimental models of NMDA receptors (both recombinant and native). The second part of the thesis focused on the modulation of NMDA receptors function by steroid compounds derived from pregnanolone sulfate, an endogenously occuring neurosteroid. We tested 21 steroids that showed various degree of ability to inhibit (or, in one case, potentiate) the current...
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Structure and function of the vanilloid receptor TRPV1
Sušánková, Klára ; Vlachová, Viktorie (advisor) ; Kršiak, Miloslav (referee) ; Chvátal, Alexandr (referee)
2 11.. SSuummmmaarryy The vanilloid receptor (TRPV1) plays a role of the polymodal detector of nociceptive stimuli in a subset of small and medium sized primary sensory neurons in mammals. This channel can be activated by vanilloid compounds, low pH, and noxious heat, and its function is modulated by a wide range of endogenous and exogenous agents. Our results demonstrate that the reducing agent dithiothreitol (DTT) strongly potentiates both the native and recombinant rat TRPV1 channel when applied at millimolar concentrations to the external solution under intact whole-cell conditions. Since the effects of DTT were almost immediate, dose-dependent, and reversible, the contribution of extracellular cysteine residues within the putative pore-loop region of TRPV1, Cys616, Cys621, and Cys634 has been proposed. We show that the chemical modification of TRPV1 by both reducing and oxidizing agents leads to an increased response to heat. In addition, we identify the extracellularly located cysteine at position 621 which contributes to the DTT-induced potentiation of heat-activated currents mediated by TRPV1. Our data also indicate that capsaicin concentration is radically altered by the presence of oxidizing agents. More generally, the redox-active substances can substantially affect the activity of TRPV1 channels...
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The electroencephalographic changes in animal serotonergic model of psychosis-the study of EEG connectivity in relation to behavior
Tylš, Filip ; Páleníček, Tomáš (advisor) ; Mareš, Pavel (referee) ; Chvátal, Alexandr (referee)
The present thesis deals with the electrophysiological and behavioral correlates of the effects of serotonergic psychedelics in an animal model of psychosis. In the general part, we describe the phenomenology and neurobiology of psychotic diseases and the altered states of consciousness induced by serotonergic psychedelics. Furthermore, we outline the pharmacological models of acute psychosis with a focus on serotonergic substances, particularly the active substances from hallucinogenic mushroom - the indolamine psilocybin and its active metabolite psilocin. We briefly explain the method of quantitative electroencephalography (QEEG) and summarize the main findings of QEEG in animals and humans intoxicated by serotonergic psychedelics. The experimental part of the thesis describes the pharmacokinetics of psilocin, its effects on the behavioral pattern, locomotion and sensorimotor processing of information, as well as sex differences in the behavioral response. A medium dose of psilocin caused atypical behavioral figures, decreased locomotion and disturbance in sensorimotor processing of information, with the females being more resistant to this effect. Another focus of the thesis is the dynamics of QEEG changes in time (EEG absolute power spectra and EEG coherences), as recorded from the cortex of...
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