The Orphan G Protein-Coupled Receptor GPR116 Regulates Pulmonary Surfactant Pool Size
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Bridges, James P., Ludwig, Marie-Gabrielle, Mueller, Matthias, Kinzel, Bernd, Sato, Atsuyasu, Xu, Yan, Whitsett, Jeffery A. and Ikegami, Machiko (2013) The Orphan G Protein-Coupled Receptor GPR116 Regulates Pulmonary Surfactant Pool Size. American Journal of Respiratory Cell and Molecular Biology. ISSN 1044-1549
Abstract
Pulmonary surfactant levels within the alveoli are tightly regulated to maintain lung volumes and
promote efficient gas exchange across the air/blood barrier. Both quantitative and qualitative
abnormalities in surfactant are associated with severe lung diseases in children and adults.
While the cellular and molecular mechanisms that control surfactant metabolism have been
studied intensively, the critical molecular pathway(s) that senses and regulates endogenous
surfactant levels within the alveolus have not been identified and constitute a fundamental
knowledge gap in the field. In this study, we demonstrate that expression of an orphan G
protein-coupled receptor, GPR116, in the murine lung is developmentally regulated, reaching
maximal levels one day following birth, and is highly expressed on the apical surface of alveolar
type I and type II epithelial cells. To define the physiological role of GPR116 in vivo, mice with a
targeted mutation of the Gpr116 locus, Gpr116Δexon17, were generated. Gpr116Δexon17 mice
developed a profound accumulation of alveolar surfactant phospholipids at 4 weeks of age (12-
fold) that is further increased at 20 weeks of age (30-fold). Surfactant accumulation in
Gpr116Δexon17 mice was associated with increased SatPC secretion at 4 weeks and the
presence of enlarged, lipid-laden macrophages, neutrophilia and alveolar destruction at 20
weeks. Through microarray analyses, we demonstrate that P2RY2, a purinergic receptor known
to mediate surfactant secretion, was induced in Gpr116Δexon17 type II cells. Collectively, these
data suggest that GPR116 functions as molecular sensor of alveolar surfactant lipid pool sizes
by regulating surfactant secretion from alveolar type II cells.
| Item Type: | Article |
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| Keywords: | pulmonary surfactant, G protein-coupled receptors, GPR116, surfactant metabolism, alveolar epithelium, saturated phosphatidylcholine |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/8898 |