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The role of the secondary messenger NAADP in physiological and pathological calcium signalling in pancreatic acinar cells

Charlesworth, Martyn 2017. The role of the secondary messenger NAADP in physiological and pathological calcium signalling in pancreatic acinar cells. PhD Thesis, Cardiff University.
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Acute Pancreatitis (AP) is inflammatory disease characterised by the pathological activation of the digestive enzymes and extensive necrosis of the pancreases and surrounding tissue, which currently has no effective treatment. Pathological agents like the bile acid taurolithocholic acid-3-sulfate (TLC-S) have been shown to induce necrosis of pancreatic acinar cells by causing intracellular calcium (Ca2+) to reach cytotoxic concentrations. TLC-S acts on elements of the secondary Ca2+ messenger pathways normally used in physiological signalling to achieve these Ca2+ increases. Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most novel of these secondary Ca2+ messengers to be identified and several recent advancements have been made regarding its activity. This study has used these advancements to better characterise NAADP-induced Ca2+ release in PAC, and its role in both physiological and pathological Ca2+ signalling. NAADP-induced Ca2+ release was found to involve the activity of both Two-pore channel (TPC) and Ryanodine receptor (RyR) Ca2+ channels; with a varying involvement of the 2 TPC and 3 RyR isoforms. The NAADP antagonist Ned-19 completely inhibited Ca2+ responses to a physiological concentration of the secretagogue cholecystokinin (CCK) and had a protective effect against a pathological concentration of CCK. The size of the Ca2+ response to TLC-S was significantly inhibited in the presence of Ned-19, and the antagonist significantly reduced the amount of necrosis induced. Another related bile acid, cholate, was found to have a similar necrotic effect to PAC as a result of pathological increases in cytosolic Ca2+. While neither Ned-19 or GSK-7975A (an inhibitor of store-operated Ca2+ entry) alone had a significant effect on cholate-induced necrosis, a combination of the two did have a protective effect. These findings suggest that Ned-19 may provide a potential therapeutic solution to AP, though it may need to be used in combination with inhibitors of other Ca2+ signalling to be effective.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Uncontrolled Keywords: Calcium NAADP Pancreatitis Physiology pathophysiology
Funders: Medical Research Council
Date of First Compliant Deposit: 9 October 2017
Last Modified: 06 Dec 2018 02:30

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