Projects per year
Abstract
Asthma is a heterogeneous chronic airway disease with an unmet need for improved therapeutics in uncontrolled severe disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor upregulated in asthma. The CaSR agonist, spermine, is also increased in asthmatic airways and contributes to bronchoconstriction. CaSR negative allosteric modulators (NAMs) oppose chronic airway inflammation, remodeling, and hyperresponsiveness in murine and guinea pig asthma models, but whether CaSR NAMs are effective acute bronchodilators compared with standard of care has not yet been established. Furthermore, the ability of different classes of NAMs to inhibit spermine-induced CaSR signaling or methacholine (MCh)-induced airway contraction has not been quantified. Here, we show CaSR NAMs differentially inhibit spermine-induced intracellular calcium mobilization and inositol monophosphate accumulation in HEK293 cells stably expressing the CaSR. NAMs reverse MCh-mediated airway contraction in mouse precision-cut lung slices with similar maximal relaxation compared with the standard treatment, salbutamol. Of note, the bronchodilator effects of CaSR NAMs are maintained under conditions of β2-adrenergic receptor desensitization when salbutamol efficacy is abolished. Furthermore, overnight treatment with some, but not all, CaSR NAMs prevents MCh-mediated bronchoconstriction. These findings further support the CaSR as a putative drug target and NAMs as alternative or adjunct bronchodilators in asthma.
Original language | English |
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Pages (from-to) | 182-196 |
Number of pages | 15 |
Journal | American Journal of Respiratory Cell and Molecular Biology |
Volume | 69 |
Issue number | 2 |
DOIs | |
Publication status | Published - 1 Aug 2023 |
Keywords
- asthma
- bronchodilator
- CaSR
- G protein–coupled receptor
- precision-cut lung slice
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ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery
Sexton, P., Rouiller, I., Wootten, D., van Oijen, A., Parker, M. W., Lucet, I., Griffin, M. D. W., Adams, D. J., Czabotar, P. E., Flocco, M., Han, S., Shepherd, R., Ciferri, C., Williams, P. A., Brown, D., Schreuder, H., Reedtz-Runge, S., Drinkwater, C., Howard, B. L., Betigeri, G., Pryor, E., How, J. & Christopoulos, T.
Boehringer Ingelheim (Germany), AstraZeneca (United Kingdom)
23/03/21 → 23/03/27
Project: Research
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Simultaneously targeting airway contraction and fibrosis as a new therapeutic strategy for asthma
Bourke, J., Royce, S., Bardin, P., Westall, G., Grainge, C., Oliver, B. G., Samuel, C. & Wadsworth, S.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/19 → 31/12/21
Project: Research
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Towards the rational design of calcium sensing receptor allosteric modulators for the treatment of osteoporosis and calcium handling disorders
Leach, K., Gregory, K., Conigrave, A., Capuano, B., Kufareva, I., Thakker, R. & Hannan, F. M.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/18 → 31/12/21
Project: Research