Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling

Kari Brown, Alyssa Filuta, Marie Gabrielle Ludwig, Klaus Seuwen, Julian Jaros, Solange Vidal, Kavisha Arora, Anjaparavanda P. Naren, Kathirvel Kandasamy, Kaushik Parthasarathi, Stefan Offermanns, Robert J. Mason, William E. Miller, Jeffrey A. Whitsett, James P. Bridges

Research output: Contribution to journalArticle

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Abstract

Pulmonary function is dependent upon the precise regulation of alveolar surfactant. Alterations in pulmonary surfactant concentrations or function impair ventilation and cause tissue injury. Identification of the molecular pathways that sense and regulate endogenous alveolar surfactant concentrations, coupled with the ability to pharmacologically modulate them both positively and negatively, would be a major therapeutic advance for patients with acute and chronic lung diseases caused by disruption of surfactant homeostasis. The orphan adhesion GPCR GPR116 (also known as Adgrf5) is a critical regulator of alveolar surfactant concentrations. Here, we show that human and mouse GPR116 control surfactant secretion and reuptake in alveolar type II (AT2) cells by regulating guanine nucleotide-binding domain α q and 11 (Gq/11) signaling. Synthetic peptides derived from the ectodomain of GPR116 activated Gq/11-dependent inositol phosphate conversion, calcium mobilization, and cortical F-actin stabilization to inhibit surfactant secretion. AT2 cell-specific deletion of Gnaq and Gna11 phenocopied the accumulation of surfactant observed in Gpr116-/- mice. These data provide proof of concept that GPR116 is a plausible therapeutic target to modulate endogenous alveolar surfactant pools to treat pulmonary diseases associated with surfactant dysfunction.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number11
DOIs
StatePublished - Jun 2 2017

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Surface-Active Agents
Homeostasis
Lung
Lung Diseases
Pulmonary Surfactants
Orphaned Children
Inositol Phosphates
Guanine Nucleotides
Ventilation
Actins
Chronic Disease
Calcium
Peptides
Wounds and Injuries
Therapeutics

Cite this

Brown, K., Filuta, A., Ludwig, M. G., Seuwen, K., Jaros, J., Vidal, S., ... Bridges, J. P. (2017). Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling. JCI insight, 2(11). https://doi.org/10.1172/jci.insight.93700

Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling. / Brown, Kari; Filuta, Alyssa; Ludwig, Marie Gabrielle; Seuwen, Klaus; Jaros, Julian; Vidal, Solange; Arora, Kavisha; Naren, Anjaparavanda P.; Kandasamy, Kathirvel; Parthasarathi, Kaushik; Offermanns, Stefan; Mason, Robert J.; Miller, William E.; Whitsett, Jeffrey A.; Bridges, James P.

In: JCI insight, Vol. 2, No. 11, 02.06.2017.

Research output: Contribution to journalArticle

Brown, K, Filuta, A, Ludwig, MG, Seuwen, K, Jaros, J, Vidal, S, Arora, K, Naren, AP, Kandasamy, K, Parthasarathi, K, Offermanns, S, Mason, RJ, Miller, WE, Whitsett, JA & Bridges, JP 2017, 'Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling', JCI insight, vol. 2, no. 11. https://doi.org/10.1172/jci.insight.93700
Brown, Kari ; Filuta, Alyssa ; Ludwig, Marie Gabrielle ; Seuwen, Klaus ; Jaros, Julian ; Vidal, Solange ; Arora, Kavisha ; Naren, Anjaparavanda P. ; Kandasamy, Kathirvel ; Parthasarathi, Kaushik ; Offermanns, Stefan ; Mason, Robert J. ; Miller, William E. ; Whitsett, Jeffrey A. ; Bridges, James P. / Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling. In: JCI insight. 2017 ; Vol. 2, No. 11.
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