Essential Regulation of Lung Surfactant Homeostasis by the Orphan G Protein-Coupled Receptor GPR116
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
Mi Young Yang
Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, MD 21702, USA
Mary Beth Hilton
Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, MD 21702, USA
Steven Seaman
Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, MD 21702, USA
Diana C. Haines
Veterinary Pathology Section, Pathology/Histotechnology Laboratory, SAIC-Frederick, FNLCR, National Cancer Institute (NCI), Frederick, MD 21702, USA
Kunio Nagashima
Electron Microscopy Laboratory, Advanced Technology Program, SAIC-Frederick, FNLCR, National Cancer Institute (NCI), Frederick, MD 21702, USA
Christina M. Burks
Veterinary Pathology Section, Pathology/Histotechnology Laboratory, SAIC-Frederick, FNLCR, National Cancer Institute (NCI), Frederick, MD 21702, USA
Lino Tessarollo
Neural Development Section, MCGP, CCR, National Cancer Institute (NCI), Frederick, MD 21702, USA
Pavlina T. Ivanova
Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
H. Alex Brown
Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Todd M. Umstead
Department of Pediatrics and Center for Host defense, Inflammation, and Lung Disease Research, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Joanna Floros
Department of Pediatrics and Center for Host defense, Inflammation, and Lung Disease Research, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Zissis C. Chroneos
Department of Pediatrics and Center for Host defense, Inflammation, and Lung Disease Research, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Brad St. Croix
Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, MD 21702, USA
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.
