The insulin-like peptide INS-27 mediates a muscle-to-neuron feedback signal coupling muscle activity with AMPA receptor trafficking.
Regulation of AMPA Receptor (AMPAR) levels at synapses controls synaptic strength and is a major mechanism underlying learning and memory. Growing evidence indicates that AMPAR trafficking can be regulated by extracellular factors. Here, we show that the insulin-like peptide INS-27 mediates a muscle...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-07-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1011786 |
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| Summary: | Regulation of AMPA Receptor (AMPAR) levels at synapses controls synaptic strength and is a major mechanism underlying learning and memory. Growing evidence indicates that AMPAR trafficking can be regulated by extracellular factors. Here, we show that the insulin-like peptide INS-27 mediates a muscle-to-neuron signal that promotes surface levels of the C. elegans AMPAR GLR-1 at synapses in pre-motor AVA interneurons that reside two synaptic layers upstream of the neuromuscular junction. Mutants lacking cholinergic neuromuscular signaling or muscle activity trigger an increase in surface GLR-1 levels in upstream AVA neurons. Genetic data suggest that this signal is dependent on the dense-core vesicle regulator unc-31/CAPS, the insulin-like peptide INS-27, which is one of the most highly expressed neuropeptides in muscle, and the Insulin/IGF-1 receptor DAF-2. ins-27 loss-of-function mutants exhibit decreased surface GLR-1 levels and defects in glutamatergic behavior. Further, loss of neuromuscular junction signaling stimulates secretion of INS-27 from muscle in an unc-31/CAPS-dependent manner. Our data support a model in which INS-27 is released from muscle and signals via DAF-2/Insulin/IGF-1 receptors to promote surface levels of GLR-1 in AVA neurons. Our study reveals a potential feedback signal that couples muscle activity with surface AMPARs in upstream neurons. |
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| ISSN: | 1553-7390 1553-7404 |