title: Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma.
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.
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
authors.forename: Polina L
authors.initials: PL
authors.lastname: Yarova
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Alecia L
authors.initials: AL
authors.lastname: Stewart
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Venkatachalem
authors.initials: V
authors.lastname: Sathish
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Britt
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Division of Pharmacology, Cardiff University, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3XF, UK.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: P Lowe
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Freeman
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Bharathi
authors.initials: B
authors.lastname: Aravamudan
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Kita
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Brennan
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Schepelmann
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Davies
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
authors.forename: Sun
authors.initials: S
authors.lastname: Yung
authors.affiliation: Division of Pharmacology, Cardiff University, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3XF, UK.
authors.forename: Zakky
authors.initials: Z
authors.lastname: Cholisoh
authors.affiliation: Division of Pharmacology, Cardiff University, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3XF, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Kidd
authors.affiliation: Division of Pharmacology, Cardiff University, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3XF, UK.
authors.forename: William R
authors.initials: WR
authors.lastname: Ford
authors.affiliation: Division of Pharmacology, Cardiff University, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3XF, UK.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Broadley
authors.affiliation: Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes MK7 6AA, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Rietdorf
authors.affiliation: Department of Medicine, UCSF School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Mohd E
authors.initials: ME
authors.lastname: Bin Khayat
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Donald T
authors.initials: DT
authors.lastname: Ward
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, London SE1 9RT, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Corrigan
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, London SE1 9RT, UK.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: T Ward
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kemp
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA. riccardi@cf.ac.uk prakash.ys@mayo.edu.
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. riccardi@cf.ac.uk prakash.ys@mayo.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Riccardi
mesh_terms: D000485:Allergens / Q000737:chemistry; D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D001706:Biopsy; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D016084:Bronchoconstriction; D002412:Cations; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D006967:Hypersensitivity / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000485:Allergens; D002412:Cations; D044169:Receptors, Calcium-Sensing; D048051:p38 Mitogen-Activated Protein Kinases