ADGRF5 and lung disorder: While the endogenous ligand or the biological process(es) leading to displacement and/or conformational change of the non-covalently linked N-terminal domain and subsequent GPR116 activation in vivo remain unknown, our data advance the mechanistic understanding of GPR116 activation in the context of pulmonary surfactant homeostasis and may facilitate the development of novel receptor modulators that can be used to treat clinically relevant lung diseases.