Tree-Booker, Claire (2011) TRPC Channels in human mast cells. PhD thesis, University of Sheffield.
Temporary Embargo (access restricted until embargo expiry date) until November 2018.
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 cross-linking 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.
|Item Type:||Thesis (PhD)|
|Academic Units:||The University of Sheffield > Faculty of Science (Sheffield) > Biomedical Science (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Biomedical Science (Sheffield)
|Depositing User:||Dr Claire Tree-Booker|
|Date Deposited:||09 Dec 2011 15:51|
|Last Modified:||08 Aug 2013 08:47|