Essential Regulation of Lung Surfactant Homeostasis by the Orphan G Protein-coupled Receptor GPR116

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2013 May 21

PMID 23684610

Citations 42

Authors

Mi Young Yang

Mary Beth Hilton

Steven Seaman

Diana C Haines

Kunio Nagashima

Christina M Burks

Lino Tessarollo

Pavlina T Ivanova

H Alex Brown

Todd M Umstead

Joanna Floros

Zissis C Chroneos

Brad St Croix

Affiliations

Soon will be listed here.

Abstract

GPR116 is an orphan seven-pass transmembrane receptor whose function has been unclear. Global disruption of the Gpr116 gene in mice revealed an unexpected, critical role for this receptor in lung surfactant homeostasis, resulting in progressive accumulation of surfactant lipids and proteins in the alveolar space, labored breathing, and a reduced lifespan. GPR116 expression analysis, bone marrow transplantation studies, and characterization of conditional knockout mice revealed that GPR116 expression in ATII cells is required for maintaining normal surfactant levels. Aberrant packaging of surfactant proteins with lipids in the Gpr116 mutant mice resulted in compromised surfactant structure, function, uptake, and processing. Thus, GPR116 plays an indispensable role in lung surfactant homeostasis with important ramifications for the understanding and treatment of lung surfactant disorders.

Citing Articles

Mechanosensitive adhesion G protein-coupled receptors: Insights from health and disease.

Sun S, Wang W Genes Dis. 2025; 12(3):101267.

PMID: 39935605 PMC: 11810715. DOI: 10.1016/j.gendis.2024.101267.

The adhesion-GPCR ADGRF5 fuels breast cancer progression by suppressing the MMP8-mediated antitumorigenic effects.

Wu Y, Liu H, Sun Z, Liu J, Li K, Fan R Cell Death Dis. 2024; 15(6):455.

PMID: 38937435 PMC: 11211477. DOI: 10.1038/s41419-024-06855-8.

The repertoire and structure of adhesion GPCR transcript variants assembled from publicly available deep-sequenced human samples.

Kuhn C, Stenzel U, Berndt S, Liebscher I, Schoneberg T, Horn S Nucleic Acids Res. 2024; 52(7):3823-3836.

PMID: 38421639 PMC: 11039983. DOI: 10.1093/nar/gkae145.

The adhesion GPCR GPR116/ADGRF5 has a dual function in pancreatic islets regulating somatostatin release and islet development.

Rothe J, Kraft R, Ricken A, Kaczmarek I, Matz-Soja M, Winter K Commun Biol. 2024; 7(1):104.

PMID: 38228886 PMC: 10791652. DOI: 10.1038/s42003-024-05783-9.

Lethal eosinophilic crystalline pneumonia in mice expressing a stabilized Csf2 mRNA.

Arao Y, Stumpo D, Hoenerhoff M, Tighe R, Yu Y, Sutton D FASEB J. 2023; 37(8):e23100.

PMID: 37462673 PMC: 11078221. DOI: 10.1096/fj.202300757R.

References

Abe J, Suzuki H, Notoya M, Yamamoto T, Hirose S . Ig-hepta, a novel member of the G protein-coupled hepta-helical receptor (GPCR) family that has immunoglobulin-like repeats in a long N-terminal extracellular domain and defines a new subfamily of GPCRs. J Biol Chem. 1999; 274(28):19957-64. DOI: 10.1074/jbc.274.28.19957. View

Myers D, Ivanova P, Milne S, Brown H . Quantitative analysis of glycerophospholipids by LC-MS: acquisition, data handling, and interpretation. Biochim Biophys Acta. 2011; 1811(11):748-57. PMC: 3292045. DOI: 10.1016/j.bbalip.2011.05.015. View

Ivanova P, Milne S, Byrne M, Xiang Y, Brown H . Glycerophospholipid identification and quantitation by electrospray ionization mass spectrometry. Methods Enzymol. 2007; 432:21-57. DOI: 10.1016/S0076-6879(07)32002-8. View

Borie R, Danel C, Debray M, Taille C, Dombret M, Aubier M . Pulmonary alveolar proteinosis. Eur Respir Rev. 2011; 20(120):98-107. PMC: 9487789. DOI: 10.1183/09059180.00001311. View

Shibata Y, Berclaz P, Chroneos Z, Yoshida M, Whitsett J, Trapnell B . GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity. 2001; 15(4):557-67. DOI: 10.1016/s1074-7613(01)00218-7. View

Okubo T, Knoepfler P, Eisenman R, Hogan B . Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation. Development. 2005; 132(6):1363-74. DOI: 10.1242/dev.01678. View

Sakagami T, Uchida K, Suzuki T, Carey B, Wood R, Wert S . Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis. N Engl J Med. 2010; 361(27):2679-81. PMC: 4174270. DOI: 10.1056/NEJMc0904077. View

Raghavendran K, Willson D, Notter R . Surfactant therapy for acute lung injury and acute respiratory distress syndrome. Crit Care Clin. 2011; 27(3):525-59. PMC: 3153076. DOI: 10.1016/j.ccc.2011.04.005. View

Lieber M, Smith B, Szakal A, Todaro G . A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer. 1976; 17(1):62-70. DOI: 10.1002/ijc.2910170110. View

10.

Seaman S, Stevens J, Yang M, Logsdon D, Graff-Cherry C, St Croix B . Genes that distinguish physiological and pathological angiogenesis. Cancer Cell. 2007; 11(6):539-54. PMC: 2039723. DOI: 10.1016/j.ccr.2007.04.017. View

11.

Mulugeta S, Gray J, Notarfrancesco K, Gonzales L, Koval M, Feinstein S . Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3. J Biol Chem. 2002; 277(25):22147-55. DOI: 10.1074/jbc.M201812200. View

12.

Malur A, Huizar I, Wells G, Barna B, Malur A, Thomassen M . Lentivirus-ABCG1 instillation reduces lipid accumulation and improves lung compliance in GM-CSF knock-out mice. Biochem Biophys Res Commun. 2011; 415(2):288-93. DOI: 10.1016/j.bbrc.2011.10.043. View

13.

Lewis J, Veldhuizen R . The future of surfactant therapy during ALI/ARDS. Semin Respir Crit Care Med. 2006; 27(4):377-88. DOI: 10.1055/s-2006-948291. View

14.

Tang X, Wang Y, Li D, Luo J, Liu M . Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. Acta Pharmacol Sin. 2012; 33(3):363-71. PMC: 4077139. DOI: 10.1038/aps.2011.210. View

15.

St Croix B, Rago C, Velculescu V, Traverso G, Romans K, Montgomery E . Genes expressed in human tumor endothelium. Science. 2000; 289(5482):1197-202. DOI: 10.1126/science.289.5482.1197. View

16.

Elhalwagi B, Zhang M, Ikegami M, Iwamoto H, Morris R, Miller M . Normal surfactant pool sizes and inhibition-resistant surfactant from mice that overexpress surfactant protein A. Am J Respir Cell Mol Biol. 1999; 21(3):380-7. DOI: 10.1165/ajrcmb.21.3.3676. View

17.

Carey B, Trapnell B . The molecular basis of pulmonary alveolar proteinosis. Clin Immunol. 2010; 135(2):223-35. PMC: 2866141. DOI: 10.1016/j.clim.2010.02.017. View

18.

Nanda A, Carson-Walter E, Seaman S, Barber T, Stampfl J, Singh S . TEM8 interacts with the cleaved C5 domain of collagen alpha 3(VI). Cancer Res. 2004; 64(3):817-20. DOI: 10.1158/0008-5472.can-03-2408. View

19.

Malur A, Baker A, McCoy A, Wells G, Barna B, Kavuru M . Restoration of PPARγ reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice. Am J Physiol Lung Cell Mol Physiol. 2010; 300(1):L73-80. DOI: 10.1152/ajplung.00128.2010. View

20.

Trapnell B, Whitsett J, Nakata K . Pulmonary alveolar proteinosis. N Engl J Med. 2003; 349(26):2527-39. DOI: 10.1056/NEJMra023226. View