Activation of GPR116/ADGRF5 by its tethered agonist requires key amino acids in extracellular loop 2 of the transmembrane region

摘要: The mechanistic details of the tethered agonist mode activation for adhesion GPCRs has not been completely deciphered. We set out to investigate physiologic importance autocatalytic cleavage upstream agonistic peptide sequence, an event necessary NTF displacement and subsequent receptor activation. To examine this hypothesis, we characterized agonist-mediated GPR116 in vitro vivo. A knock-in mouse expressing a non-cleavable mutant phenocopies pulmonary phenotype knock-out mice, demonstrating that is indispensable function Using site-directed mutagenesis species swapping approaches identified key conserved amino acids sequence extracellular loops 2/3 (ECL2/3). further highlight residues transmembrane7 (TM7) mediate stronger signaling versus human recapitulate these findings model supporting agonist:ECL2 interactions Grant supportThis work was supported part by HL131634 (JPB) from National Heart, Lung Blood Institute Institutes Health.