# Identification of mechanisms that regulate postsynaptic receptor abundance at the neuromuscular junction

> **NIH NIH P20** · UNIVERSITY OF DELAWARE · 2021 · $180,976

## Abstract

Project Summary
At the neuromuscular junction (NMJ), postsynaptic nicotinic acetylcholine receptors (AChRs) transduce a
chemical signal released from a cholinergic motor neuron into an electrical signal to induce muscle contraction.
Defects in cholinergic signaling are the primary cause of severe muscle weakness observed in individuals with
congenital myasthenic syndromes and the autoimmune syndrome myasthenia gravis. In addition, clinical
features of some congenital myopathies and muscular dystrophies suggest underlying cholinergic signaling
defects. Together, this highlights the importance of determining how signaling through AChRs is regulated at the
NMJ. While mechanisms that lead to the clustering of postsynaptic AChRs have been well studied, little is known
about how receptor insertion and endocytosis is controlled to maintain synaptic efficacy.
The body wall muscles in the model organism C. elegans are functionally comparable to vertebrate skeletal
muscles. Sinusoidal locomotion occurs as a result of activation of postsynaptic AChRs on one side of the animal,
which causes muscle contraction, while simultaneous stimulation of GABAA receptors on the opposite side of
the animal triggers muscle relaxation. To identify novel factors that regulate postsynaptic cholinergic signaling
we performed a genome wide RNAi screen for gene knockdowns that altered C. elegans sensitivity to the AChR
agonist levamisole. One knockdown that caused levamisole hypersensitivity was epn-1, the homolog of
mammalian Epsin, which functions to recruit specific cargoes and induce membrane curvature during
endocytosis. We discovered that loss of epn-1 resulted in an increase in AChRs, but surprisingly, a decrease in
GABAA receptors on the plasma membrane. This led us to hypothesize that EPN-1 as well as some of the other
screen isolates regulate trafficking of postsynaptic receptors to maintain appropriate neuromuscular
transmission. Our overarching goal is to define the mechanisms that control postsynaptic receptor abundance
and localization at the NMJ by characterizing genes identified in our screen. We will use an integrated approach,
performing innovative genetic, imaging, biomechanical profiling, and optogenetic experiments. Our study will
enable us to develop a broad understanding of mechanisms underlying postsynaptic receptor trafficking at the
NMJ, as well as identify novel gene targets for future studies and therapeutic design.
I will build upon my strong foundation in genetics, neuroscience, physiology, and C. elegans research to develop
a comprehensive and meaningful research program under the mentorship of Dr. Velia Fowler and Dr. Robert
Akins who have expertise in skeletal muscle contraction and NMJ development in children with muscle diseases,
respectively. This research plan will be carried out in the Department of Biological Sciences and excellent core
facilities at the University of Delaware. The Delaware Center for Musculoskeletal Research will provide ...

## Key facts

- **NIH application ID:** 10091026
- **Project number:** 1P20GM139760-01
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Jessica E Tanis
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $180,976
- **Award type:** 1
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091026

## Citation

> US National Institutes of Health, RePORTER application 10091026, Identification of mechanisms that regulate postsynaptic receptor abundance at the neuromuscular junction (1P20GM139760-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10091026. Licensed CC0.

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