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Extrasynaptic acetylcholine signaling through a muscarinic receptor regulates cell migration

Kato, Mihoko and Kolotuev, Irina and Cunha, Alexandre and Gharib, Shahla and Sternberg, Paul W. (2021) Extrasynaptic acetylcholine signaling through a muscarinic receptor regulates cell migration. Proceedings of the National Academy of Sciences of the United States of America, 118 (1). Art. No. e1904338118. ISSN 0027-8424. PMCID PMC7817160. doi:10.1073/pnas.1904338118.

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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 Caenorhabditis elegans. 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 Gαq/egl-30, PLCβ/egl-8, and TRIO/unc-73. 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.

Item Type:Article
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URLURL TypeDescription Information CentralArticle
Kato, Mihoko0000-0003-3827-8879
Kolotuev, Irina0000-0003-1433-8048
Cunha, Alexandre0000-0002-2541-6024
Sternberg, Paul W.0000-0002-7699-0173
Additional Information:© 2021 The Author(s). Published under the PNAS license. Contributed by Paul W. Sternberg, September 6, 2020 (sent for review March 20, 2019; reviewed by Reinhard W. Köster and James B. Rand) Published in issue January 5, 2021. Published first December 23, 2020. We thank laboratory members, particularly Pei Yin Shih, Ravi Nath, and Han Wang, for comments on the paper. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (grant P40 OD010440), and by the C. elegans Gene Knockout Project at the Oklahoma Medical Research Foundation, which was part of the International C. elegans Gene Knockout Consortium. For image collection and analysis, we used the Caltech Biological Imaging Facility and the Center for Advanced Methods in Biological Image Analysis. We received microscopy training from Dr. Andres Collazo and Huygens software training from Say-Tar Goh. Dr. Rene Garcia, Dr. Derek Sieburth, and Dr. Kenneth Miller kindly provided strains and reagents. This work was supported by HHMI with whom P.W.S. was an investigator and by US Public Health Service NIH, Eunice Kennedy Shriver Institute of Child Health and Human Development grant R01 HD091327 to P.W.S. and M.K. Data Availability. All study data are included in the article and supporting information. Author contributions: M.K., I.K., and P.W.S. designed research; M.K., I.K., and S.G. performed research; M.K. and A.C. contributed new reagents/analytic tools; M.K., I.K., and A.C. analyzed data; and M.K. and P.W.S. wrote the paper. Reviewers: R.W.K., Technische Universität Braunschweig; and J.B.R., University of Oklahoma Health Sciences Center. The authors declare no competing interest. This article contains supporting information online at
Funding AgencyGrant Number
NIHP40 OD010440
Oklahoma Medical Research FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)047-101
Issue or Number:1
PubMed Central ID:PMC7817160
Record Number:CaltechAUTHORS:20201224-085807779
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Official Citation:Extrasynaptic acetylcholine signaling through a muscarinic receptor regulates cell migration Mihoko Kato, Irina Kolotuev, Alexandre Cunha, Shahla Gharib, Paul W. Sternberg Proceedings of the National Academy of Sciences Jan 2021, 118 (1) e1904338118; DOI: 10.1073/pnas.1904338118
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107278
Deposited By: George Porter
Deposited On:04 Jan 2021 14:56
Last Modified:16 Nov 2021 19:01

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