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Activation of ion channels by ischaemia related factors

Allen, Nicola Jane; (2003) Activation of ion channels by ischaemia related factors. Doctoral thesis (Ph.D.), University College London (United Kingdom). Green open access

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This thesis examines: (1) the mechanism of release and actions of the inhibitory neurotransmitter GABA during ischaemia, (2) the factors which determine the time taken for ion gradients to run down and trigger neurotransmitter release during metabolic inhibition, and (3) modulation of Acid Sensing Ion Channels (ASICs) by factors released during ischaemia. Ischaemia was simulated in hippocampal slices by removal of oxygen and glucose and chemical inhibition of glycolysis and mitochondrial electron transport. CAl neurons were whole-cell patch-clamped and their GABAA receptors were used to monitor GABA release during ischaemia. I found that in the first few minutes of ischaemia GABA is released via spontaneous exocytosis, then after the anoxic depolarisation (AD) GABA is released via reversal of neuronal GABA transporters. Chloride entry, through GABAA receptors activated by the released GABA, first protects neurons by hyperpolarising them, but then contributes to the potentially damaging neuronal swelling that occurs at the time of the AD. After the AD, GABAA receptors are desensitised via calcium influx through NMDA receptors. By using different manipulations to block ATP production by mitochondria or by glycolysis, I investigated the possible energy stores which temporarily sustain ATP production during metabolic inhibition. I showed that a substantial delay in the occurrence of the AD (and associated transmitter release) is conferred by ATP production from glycogen or from external glucose (in the absence of oxygen), and from pyruvate or citric acid cycle intermediates (in the presence of oxygen). ASICs are activated by a decrease in the extracellular pH. I found that the peak H+-evoked current in isolated cerebellar Purkinje neurons was potentiated by factors which are released or altered during ischaemia, including membrane stretch, arachidonic acid, lactate and the neuropeptide FMRFamide. Arachidonic acid also induced a sustained current in the presence of acidic pH in the majority of cells recorded from, leading to a maintained cation influx which may contribute to cell swelling and death. These data show that the activation of ASICs reflects the integration of multiple signals which are present during ischaemia.

Type: Thesis (Doctoral)
Qualification: Ph.D.
Title: Activation of ion channels by ischaemia related factors
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: (UMI)AAIU644124; Biological sciences; GABA
URI: https://discovery.ucl.ac.uk/id/eprint/10103374
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