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dc.contributor.supervisor Mayne, Michael (Pharmacology and Therapeutics) en
dc.contributor.author Grant, Jeff
dc.date.accessioned 2008-09-11T21:58:15Z
dc.date.available 2008-09-11T21:58:15Z
dc.date.issued 2008-09-11T21:58:15Z
dc.identifier.uri http://hdl.handle.net/1993/3073
dc.description.abstract This thesis focuses on the regulation of the ubiquitous second messenger Ca2+ in neuronal physiology and disease. Ca2+ signalling in neurons is regulated by ion channels located in the plasma membrane, as well as in the endoplasmic reticulum (ER) and mitochondrial membranes. Ca2+ signalling is essential for numerous cellular processes, including neuronal excitability, neurotransmitter release, synaptic plasticity, and induction of cell death. Age-related disruptions in Ca2+ signalling may contribute to decline of cognitive function and motor control associated with aging. Furthermore, disruption in neuronal Ca2+ signalling is implicated in several neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). In this thesis, I studied neuronal Ca2+ signalling and how it is affected in neurodegenerative disease. First, I examined the role of the ER Ca2+ binding protein Calreticulin (CRT) in AD. CRT is involved in regulation of ER Ca2+ signalling and modulation of susceptibility to cell death. I found that there was an increase in the expression of CRT in in vitro and in vivo models of AD. However, increased levels of CRT did not alter susceptibility of neuronal cells to death induced by AD-related stressors. Second, I examined the role of X-Linked Inhibitor of Apoptosis Protein (XIAP) in the modulation of neuronal Ca2+ signalling. I found that overexpression of XIAP in neuronal cells modified Ca2+ signalling by decreasing Ca2+ flux through multiple plasma membrane and ER channels. These effects appear to be independent of caspase inhibition, which is one of the ways that XIAP can inhibit apoptosis. Third, I examined a compound found in green tea, L-theanine, a glutamate receptor antagonist that is protective in models of excitotoxic neuronal injury. I found that 24 hour L-theanine treatment reduces the amount of Ca2+ released from neuronal intracellular stores in response to both glutamate stimulation and passive leak through ER channels. An acute 30 minute L-theanine treatment had similar effects. In conclusion, these observations further the understanding of the regulation of Ca2+ signalling in neurons and may lead to novel therapeutic strategies in neurodegenerative disease. en
dc.format.extent 1341834 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject calcium en
dc.subject neuron en
dc.subject XIAP en
dc.subject Calreticulin en
dc.subject L-Theanine en
dc.subject Alzheimer's disease en
dc.subject neurodegeneration en
dc.title Modulators of calcium signalling in neuronal physiology and disease en
dc.degree.discipline Pharmacology and Therapeutics en
dc.contributor.examiningcommittee Fernyhough, Paul (Pharmacology and Therapeutics) Parkinson, Fiona (Pharmacology and Therapeutics) Amara, Francis (Biochemistry and Medical Genetics) Cashman, Neil (University of British Columbia) en
dc.degree.level Doctor of Philosophy (Ph.D.) en
dc.description.note October 2008 en


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