The tetraspanin Tspan18 regulates GPVI induced platelet activation and Ca\(^2\)\(^+\) mobilisation

Platelet activation and subsequent thrombus formation are important for preventing excessive blood loss at sites of vascular injury, a process termed haemostasis. However, excessive platelet activation at sites of atherosclerotic plaque rupture can lead to thrombus formation, which may occlude the vessel and cause heart attack or stroke. The platelet collagen receptor GPVI is essential for thrombus formation, but is largely dispensable for haemostasis. \n \nTetraspanins are transmembrane proteins which compartmentalise the membrane through formation of dynamic tetraspanin-enriched microdomains. Due to regulation of a wide range of partner proteins, tetraspanins have been implicated in many cellular processes, including platelet activation, though most platelet tetraspanins have not been characterised. \n \nThe aim of this thesis was to investigate the novel platelet tetraspanin Tspan18, using the Tspan18 knockout mouse. Tspan18 was shown to have a role in platelet activation and platelet Ca\\(^2\\)\\(^+\\) signalling specifically downstream of GPVI. Tspan18 also appeared to have a role in haemostasis, as Tspan18 deficient mice displayed a severe bleeding phenotype. The bleeding was shown to be driven by non-haematopoietic cells and is therefore unlikely to be platelet-driven. Additionally, Tspan18-induced Ca\\(^2\\)\\(^+\\) mobilisation was shown to be dependant on functioning Orai1 Ca\\(^2\\)\\(^+\\) channels and a novel interaction between Tspan18 and the Orai family was identified. Together, these findings suggest a role for Tspan18 in platelet activation and regulation of Ca\\(^2\\)\\(^+\\) mobilisation, potentially via interaction with Orai proteins.