The β integrin modulates serotonin sensitivity via NPxY motifs to regulate egg laying and mechanosensation behaviors in C. elegans

ABSTRACT Background Integrin is an αβ heterodimeric receptor to the extracellular matrix; its binding to the matrix recruits focal adhesions to two NPxY motifs, the tyrosine phosphorylation sites in the cytoplasmic domain. Studies found that replacing tyrosines (Y) with phenylalanines (F) in the motif of β1 integrin displayed little developmental or behavioral defects. However, the tyrosine-to-alanine (A) caused embryonic lethality. Results Here we report novel functions of the NPxY motifs in C. elegans pat-3 β integrin. The membrane-proximal non-phosphorylation pat-3(Y792F) mutation caused hypersensitive egg laying in serotonin, which is more prominent than the membrane-distal NPxY 804 . The double non-phosphorylatable pat-3(YYFF) mutant exhibited serotonin hypersensitivity and defective egg retention. The phosphomimetic NPxY, pat-3(Y804E), mutant displayed a reduced egg laying in response to serotonin and fluoxetine, suggesting that the NPxY phosphorylation is associated with vulval contraction and serotonin sensitivity. Additionally, pat-3(Y792A) , pat-3(Y792F) , pat-3(Y804E), and pat-3(YYFF) mutants exhibited mechanosensation defects, demonstrating that NPxY phosphorylation regulates sensory neuron activity. Further revealed that exogenous serotonin reduced mechanosensation, while blocking serotonin secretion rescued the mechanosensation of pat-3 NPxY mutants, suggesting that integrin NPxY modulates serotonin levels in C. elegans . Conclusion Our results underscore the functional importance of pat-3 NPxY motifs in muscle and neurons, potentially linking integrin NPxY motifs to neurotransmitter response and mechanosensory functions.