Ladan Parhamifar 

Sigalling and trafficking of the cysteinyl leukotriene receptors in intestinal epithelial cells 

Academic Dissertation by due permission of the Faculy of Medicine, Lund University, Sweden 
to be defended at the main lecture hall, Pathlogy building, Malmö University Hospital , Malmö 
on Friday 23rd of January, 2009 at 09,15 for the degree of Doctor of Philosophy, 
Faculty of Medicine 

Faculty opponent; 
Prof. Catherine Godson,
College of Life Sciences, Conway Institute Belfield, Dublin 4, Ireland

Abstract 

Inflammation is a response to injury or pathogen invasion. A large proportion of the bodie's immune system is centred in the gastrointestinal tract (GI). Prolonged inflammatory conditions of the GI have been suggested to increase the risk for developing colon cancer. The cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4 are inflammatory mediators that can bind to four known receptors, two of which are the CysLT1R and CysLT2R. Inhibitors of the CysLT1R are currently used in the clinic as asthma medication. LTD4 has been shown to induce cell proliferation, survival and migration in intestinal epithelial cells (Int407) via the CysLT1R. These mechanisms are often used by cancer cells to surive and spread. Furthermore, increased expression of the CysLT1R in colon cancer patient material is correlated with a poorer survival prognosis. Conversley, increased expression of the CysLT2R is correlated with a better survival prognosis. The aim of this thesis was therefore to explore the signalling and trafficking of the cysLT1R and CysLT2R. Our results demonstrate that LTD4 via the CysLT1R can activate the enzyme cPLA2-alpha. This enzyme releases arachidonic acid, the precursor of CysLTs, from the cell membranes, upon activation. One major regulatory mechanism of GPCRs is the internalization from cell membrane upon activation. We demonstrate how LTD4 mainly internalizes CysLT1R and accumulates this receptor at the nuclear membrane and that LTC4 internalizes both the CysLT1R and CysLT2R. This information is valuable in developing potential drugtargets aqainst CysLT1 and CysLT2 in cancer and inflammation.