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The C-terminal truncated splicing variant of NK1R negatively modulates substance P-stimulated NK1R signaling
Lan Phuong Nguyen1, Duc Trung Nguyen1, Minyoung Cho1
1Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea.
Abstract:
Mammalian neurokinin 1 receptor (NK1R) exists as full-length (NK1L) and truncated (NK1S) splice variants. However, the functional role of NK1S remains controversial; therefore, we investigated their functional interplay. Using NanoBiT and co-immunoprecipitation, we demonstrate that NK1L and NK1S form heterodimeric complexes. Through this interaction, NK1S negatively modulates NK1L-mediated G protein signaling, specifically impairing Gαq coupling and Ca2+ mobilization. Conversely, NK1S enhances β-arrestin1 recruitment to NK1L, altering receptor trafficking. In A549 cells, NK1S suppressed NK1L-mediated cell migration despite sustaining ERK phosphorylation. These findings provide mechanistic evidence that NK1S can regulate NK1L through dimerization and may shift signaling bias from G proteins toward β-arrestin-linked pathways to influence cellular outcomes.
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