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Title: TRPC channels in human mast cells
Author: Tree-Booker, Claire
ISNI:       0000 0004 2722 686X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2011
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Mast cells have an important role in the immune system, but they are centrally involved in the pathophysiology of asthma, along with a number of other allergic diseases including rhinitis, eczema and irritable bowel disease (Metcalfe et al., 1997; Beaven, 2009). In the allergic response they are activated by IgE binding to high affinity receptors and subsequent crosslinking by antigen. A rise in intracellular Ca2+ is required for mast cells to become activated and release mediators into the surrounding areas, which give rise to the symptoms of allergic disease (Gilfillan & Tkaczyk, 2006). Elucidating the ion channels responsible for mast cell Ca2+ entry may unveil new therapeutic targets for the treatment of asthma and other allergic diseases. Store-operated Ca2+ entry (SOCE) is a major mechanism for mast cell Ca2+ influx and is known to involve highly Ca2+-selective Orai1 channels. TRPC channels are non-selective Ca2+ channels; TRPC1, 4 and 5 are thought to be involved in SOCE, whereas TRPC3, 6 and 7 are activated by diacylglycerol (DAG). Whilst a limited number of studies carried out in rodent mast cells suggest that TRPC channels could be important for Ca2+ entry and mediator release, their functional expression and roles in human mast cells have not been characterised. This study showed that the LAD 2 human mast cell line and primary human lung mast cells (HLMCs) express mRNA for TRPC6. TRPC6-like currents were demonstrated for the first time in HLMCs, in response to direct activation by the DAG analogue OAG, and downstream of Gq protein-coupled P2Y1 receptor stimulation by ADP. This study also revealed for the first time that TRPC1 channels are expressed in both LAD 2 cells and HLMCs, and that both TRPC1 and Orai1 channels are likely to be involved in SOCE. Importantly, this study also indicated that TRPC1 channels could be involved in Ca2+ entry and mediator release downstream of IgE receptor activation. TRPC channels could thus contribute to Ca2+ entry required for mast cell activation in allergic disease, and could represent a therapeutic target for the modulation of diseases such as asthma.
Supervisor: Seward, Elizabeth Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available