Authors: Polina L. Yarova1, Alecia L. Stewart2 *,Venkatachalem Sathish2 *,Rodney D. Britt Jr.2 *,Michael A. Thompson2 *,Alexander P. P. Lowe4 *, Michelle Freeman2, Bharathi Aravamudan2, Hirohito Kita3, Sarah C. Brennan1, Martin Schepelmann1, Thomas Davies1, Sun Yung1, Zakky Cholisoh4, Emma J. Kidd4, William R. Ford4, Kenneth J. Broadley4, Katja Rietdorf5, Wenhan Chang6, Mohd E. Bin Khayat7, Donald T. Ward7, Christopher J. Corrigan8, Jeremy P. T. Ward8, Paul J. Kemp1, Christina M. Pabelick2, Y. S. Prakash2 †, and Daniela Riccardi1 †
1School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK
2Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
3Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
4Division of Pharmacology, Cardiff University, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3XF, UK.
5Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes MK7 6AA, UK.
6Department of Medicine, UCSF School of Medicine, San Francisco, CA 94143, USA.
7Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
8Division of Asthma, Allergy and Lung Biology, King’s College London, London SE1 9RT, UK.
† Corresponding author. E-mail: firstname.lastname@example.org (D.R.); email@example.com (Y.S.P.)
* These authors contributed equally to this work.
Abstract: Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyperreactivity in mouse bronchi, and this effect was 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 up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics.
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