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Saltmarsh, Esther Joy
Languages: English
Types: Doctoral thesis
Subjects: RD
Neutrophils are at the front line of defence in humans against attack by invading pathogens. They undergo complex behaviours, many of which are controlled by changes in the concentration of cytosolic free calcium ions (Ca2+). However, the control and mechanisms of these behaviours are still the subject of much research and debate. Ca2+ is known to be important in many different cell systems. There are a plethora of Ca2+ signalling events in the "Ca2+ toolkit", but not all cells have each element. It is not fully understood elements of the toolkit that neutrophils employ to make up their well- characterised global Ca2+ changes. This thesis is an investigation into the involvement of Ca2+ in neutrophil behaviours that underlie much of their functionality, particularly focussing on subcellular Ca2+ release events (puffs) and Ca2+ signalling during neutrophil spreading on surfaces and during phagocytosis. Reports were published by Petty et al of a travelling zone of elevated Ca2+ (z-wave) in neutrophils. However, research laid out in this thesis demonstrates that these z-waves are questionable in neutrophils. Instead, conventional Ca2+ puffs and waves were seen and characterised in response to fMLP stimulation and uncaging IP3. Neutrophils undergo dramatic, rapid morphological changes during Ca2+ signals triggered by both fMLP and uncaging IP3, representative of behaviour during adhesion and extravasation. It was shown that the high concentration of Ca2+ under the plasma membrane that results from Ca2+ influx activated the protease calpain, which released the membrane from the cytoskeleton for rapid shape change. Similar signals and behaviours are seen when neutrophils are stimulated by binding of beta3-integrins. Indeed, adhesion to ICAM-1 expressing cells and phagocytosis resulted in global Ca2+ signals and Ca2+ influx accompanied by rapid shape change. However, no Ca2+ puffs were seen in these latter experiments, implying that the signalling in these conditions occurs through a different pathway, possibly PIP3. In conclusion, neutrophils utilise conventional Ca2+ signalling events (release puffs and influx waves) not z-waves to control many of their functions. They are capable of producing Ca2+ puffs, but the lack of ER means this is unlikely to be a primary signalling pathway. Binding through jS-integrins does trigger Ca2+ signals, possibly through the PIP3 pathway, but not store release. The characterisation of Ca puffs and the functionality of the Ca2+-activated protease calpain in these conditions are novel and merit future investigation. The findings in mis thesis enhance the general understanding of how neutrophil behaviours are regulated by Ca2+ and provide a new methodology for further research.

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