Calcium sensors as new therapeutic targets for asthma

Abstract

In this thesis, the effects of the two calcium -like peptides CALP1 and CALP2 on several cell types involved in asthma are examined. Furthermore, we tested the effects of these peptides in a guinea pig model for allergic asthma. Calcium is a key secondary messenger, whose function is tightly regulated by the calcium-sensing regulatory protein calmodulin (CaM). CALPs are peptides which specifically bind to the calcium -binding sites, the EF-hands, of CaM. Specific modulation of calcium and/or CaM-regulated processes provides insights into processes such as cell signalling. Specifically, CaM modulates the intracellular calcium concentration, since CaM regulates the opening and closing of calcium channels present in non-excitable cells. Asthma is a chronic airway disease characterized by airway obstruction, airway hyperresponsiveness and most importantly, inflammation. The disease affects about 10% of the population, and the prevalence is rising in many parts of the world, especially in children. Cells involved in the pathophysiology of asthma include airway epithelial cells, mast cells and inflammatory cells. In this thesis we show that CALP1 blocks mast cells mediator release, inhibits the release of epithelium-derived relaxing factors and presumably attenuates radical production by alveolar macrophages in vivo. CALP2, on the other hand, blocks mast cell mediator release, increases the release of NO by airway epithelial cells and markedly increases radical production by alveolar macrophages in vitro, and most likely also in vivo. Taken together, these peptides have both beneficial and detrimental effects on cells involved in the pathogenesis of asthma. Thus, neither CALP1 nor CALP2 seem to be candidates for therapeutic interventions in asthma. However, although more research has to be performed to elucidate the exact mechanism of action of these peptides, some indirect evidence has been obtained that store-operated calcium channels are crucial in this mechanism. Therefore, specific modulation of store-operated calcium influx might be a target for future therapy against asthma. CALPs can serve as useful tool to further explore the role of these calcium channels in asthma.