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Glutamate receptors potentiate single K-ATP channels through intracellular ATP changes

dc.contributor.advisorMironov, Sergej Dr.
dc.contributor.authorMollajew, Rustam
dc.titleGlutamate receptors potentiate single K-ATP channels through intracellular ATP changesde
dc.contributor.refereeBrose, Nils Prof. Dr.
dc.description.abstractengRett Syndrome (RTT) is a neurodevelopmental disorder caused primarily by mutations in a Mecp2 gene and exclusively affects females. RTT is one of the prevalent developmental disorders with a high frequency of occurrence (about 1:15,000 to 1:10,000) and patients are prone to gastro-intestinal disorders and about 80% have seizures. Although the genetic defect in the Mecp2 gene defines RTT, the insights from recent studies have highlighted the complex pathophysiological mechanisms that point to developmental disorder. A better understanding of the interplay of these pathophysiological mechanisms is one of the challenges in establishing of effective therapeutic strategies. In the present study, we used Mecp2-null mice as a model to examine the physiological and/or pathophysiological cellular mechanism pathways that can play important role in the development of Rett Syndrome. The main aspect of this study was to reveal the role of glutamate receptors (GluR) /K-ATP channels crosstalk in the development of RTT. Accordingly, the activities of these channels were examined in neurons from wild type (WT) and Mecp2-null mice that represent physiological and pathophysiological examples, respectively. Excessive stimulation of glutamatergic receptors can overexcite neurons. This can be dampened by K-ATP channels linking metabolic and neuronal activities. The crosstalk has not yet been examined on the single channel level. I aimed to examine how K-ATP channel activity changes after stimulation of neuronal glutamate receptors and whether those effects may be mediated through variations in the intracellular ATP levels.   In the hippocampal neurons, GluR agonists augmented the open state probability (Popen) of K-ATP channels with relative efficacy: Kainate = AMPA > NMDA > t-ACPD. Inhibition of calcium influx and chelation of intracellular calcium did not modify the GluR effects. Kainate did not augment production of reactive oxygen species measured with roGFP1. The oxidant H2O2 increased Popen about 2-fold within 1 min but the subsequent application of AMPA/Kainate produced further potentiation; in the same proportion as in the control. The data indicate that changes in the activity of K-ATP channels due to ROS and GluR stimulation have different mechanisms. GluR actions were abolished in Na+-free solutions and after blockade of Na+-K+-ATPase. GluR stimulation enhanced ATP consumption that decreased submembrane ATP levels, whereas metabolic poisoning diminished bulk ATP.  Increase of the K-ATP channel open state probabilities after GluR stimulation less in Mecp2 -/y   hippocampal neurons. It allows to speculate whether protective role attributed commonly to K-ATP channels in RTT hippocampal neurons may be less effective. I examined the role of GluR and K-ATP channels cross-talk in relation to mechanisms of epilepsy. In hippocampal organotypic slices using well established model, a seizure-like activity was evoked by removal of magnesium from bath. This was accompanied by calcium and ATP changes. The ATP responses were distinctly different in specific hippocampal regions: in dentate gyrus (DG) the neurons possessed higher ATP resting levels and showed smaller changes to epileptogenic stimuli in comparison with CA1 and CA3 areas.  ATP levels in RTT neurons were significantly higher than those measured in WT cells. This corroborates well with observations of diminished K-ATP channel open state probability. We propose that K-ATP channels and GluRs are functionally coupled and can regulate long-lasting changes of neuronal activity in the CNS neurons. The obtained data indicate that RTT symptom as propensity to seizures can be essentially contributed by improper K-ATP channel
dc.contributor.coRefereeGöpfert, Martin Prof. Dr.
dc.subject.engK-ATP channels, Glutamate receptors, intracellular ATP level, Rett Syndromede
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de

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