Mutations to the adhesion G protein-coupled receptor ADGRG1 (G1; also known as GPR56) underlie the neurological disorder bilateral frontoparietal polymicrogyria (BFPP). Disease-associated mutations in G1 studied to date are believed to induce complete loss of receptor function, either through disruption of receptor trafficking or signaling activity. Given that N-terminal truncation of G1 and other adhesion G protein-coupled receptors has been shown to significantly increase the receptors' constitutive signaling, we examined two different BFPP-inducing extracellular loop mutations (R565W and L640R) in the context of both full-length and N-terminally truncated (deltaNT) G1. Interestingly, we found that these mutations reduced surface expression of full-length G1 but not G1-deltaNT in HEK-293 cells. Moreover, the mutations ablated receptor-mediated activation of serum response factor luciferase, a classic measure of Galpha12/13-mediated signaling, but had no effect on G1-mediated signaling to nuclear factor of activated T cells (NFAT) luciferase. Given these differential signaling results, we sought to further elucidate the pathway by which G1 can activate NFAT luciferase. We found no evidence that deltaNT activation of NFAT is dependent on Galphaq/11-mediated or beta-arrestin-mediated signaling, but rather involves liberation of G beta gamma subunits and activation of calcium channels. These findings reveal that disease-associated mutations to the extracellular loops of G1 differentially alter receptor trafficking, depending on the presence of the N-terminus, and also differentially alter signaling to distinct downstream pathways.
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