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Comments on Kato M et al. (2021) Proc Natl Acad Sci U S A "Extrasynaptic acetylcholine signaling through a muscarinic receptor regulates cell migration." (0)
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Kato M, Kolotuev I, Cunha A, Gharib S, & Sternberg PW (2021). Extrasynaptic acetylcholine signaling through a muscarinic receptor regulates cell migration. Proc Natl Acad Sci U S A, 118. doi:10.1073/pnas.1904338118
Acetylcholine (ACh) promotes various cell migrations in vitro, but there are few investigations into this nonsynaptic role of ACh signaling in vivo. Here we investigate the function of a muscarinic receptor on an epithelial cell migration in <i>Caenorhabditis elegans</i> We show that the migratory gonad leader cell, the linker cell (LC), uses an M1/M3/M5-like muscarinic ACh receptor GAR-3 to receive extrasynaptic ACh signaling from cholinergic neurons for its migration. Either the loss of the GAR-3 receptor in the LC or the inhibition of ACh release from cholinergic neurons resulted in migratory path defects. The overactivation of the GAR-3 muscarinic receptor caused the LC to reverse its orientation through its downstream effectors Gq/<i>egl-30</i>, PLC/<i>egl-8</i>, and TRIO/<i>unc-73</i> This reversal response only occurred in the fourth larval stage, which corresponds to the developmental time when the GAR-3::yellow fluorescent protein receptor in the membrane relocalizes from a uniform to an asymmetric distribution. These findings suggest a role for the GAR-3 muscarinic receptor in determining the direction of LC migration.