Calcium-sensing receptor antagonists abrogate airways hyperresponsiveness and inflammation in allergic asthma

Airways hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma and are accompanied by increases in certain polycations, such as eosinophil cationic protein, whose levels in body fluids correlate with asthma severity. Here we show that polycations, or elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cAMP breakdown and p38 MAPK phosphorylation in airway smooth muscle (ASM) cells, effects prevented by CaSR antagonists, termed calcilytics. Asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than their healthy counterparts. Polycations induced hyperreactivity in mouse bronchi, effect prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is upregulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Calcilytics may represent a novel, effective asthma therapeutics