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bioRxiv · 10.1101/562041

Crosstalk with the GAR-3 receptor contributes to feeding defects in Caenorhabditis elegans eat-2 mutants

Kozlova, A.·Lotfi, M.·Okkema, P.
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Abstract

Precise signaling at the neuromuscular junction (NMJ) is essential for proper muscle contraction. In the C. elegans pharynx, acetylcholine (ACh) released from the MC and M4 motor neurons stimulates two different types of contractions in adjacent muscle cells, termed pumping and isthmus peristalsis. MC stimulates rapid pumping through the nicotinic ACh receptor EAT-2, which is tightly localized at the MC NMJ, and eat-2 mutants exhibit a slow pump rate. Surprisingly, we found that eat-2 mutants also hyperstimulated peristaltic contractions, and these are characterized by increased and prolonged Ca2+ transients in the isthmus muscles. This hyperstimulation depends on crosstalk with the GAR-3 muscarinic acetylcholine receptor as gar-3 mutation specifically suppressed the prolonged contraction and increased Ca2+ observed in eat-2 mutant peristalses. Similar GAR-3 dependent hyperstimulation was also observed in mutants lacking the ace-3 acetylcholinesterase, and we suggest that NMJ defects in eat-2 and ace-3 mutants result in ACh stimulation of extrasynaptic GAR-3 receptors in isthmus muscles. gar-3 mutation also suppressed slow larval growth and prolonged lifespan phenotypes that result from dietary restriction in eat-2 mutants, indicating that crosstalk with the GAR-3 receptor has a long-term impact on feeding behavior and eat-2 mutant phenotypes. Article SummaryAcetylcholine stimulates different contractions in adjacent muscle cells in the C. elegans pharynx called pumping and peristalsis. The signaling mechanisms stimulating pumping have been characterized, but how these mechanisms affect peristalsis is unknown. Here we examined muscle contractions and Ca2+ transients during peristalsis in wild-type animals and acetylcholine signaling mutants. Surprisingly we found that while mutants affecting the eat-2 nicotinic acetylcholine receptor exhibited reduced pumping, they also hyperstimulated peristalses. This hyperstimulation depends on crosstalk with the GAR-3 muscarinic acetylcholine receptor in adjacent cells, and it contributes to the well-characterized dietary restriction and extended adult lifespan observed in eat-2 mutants.

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Kozlova, A., Lotfi, M., Okkema, P.. 2019-02-26. Crosstalk with the GAR-3 receptor contributes to feeding defects in Caenorhabditis elegans eat-2 mutants. https://doi.org/10.1101/562041

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