# The Role of the Neuronal Membrane Proteasome in the Peripheral Nervous System and Pain Sensation

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY
While the proteasome is typically known as protein degradation machinery, it is now recognized to have
additional signaling functions in the nervous system. One poorly understood but therapeutically important role
for the proteasome is in pain regulation in the peripheral nervous system (PNS). However, the relationship of
proteasome activity to pain sensation is complex and somewhat paradoxical: proteasome inhibition has been
found to either reduce pain or to cause pain sensitization and peripheral neuropathies depending on length of
inhibition, type of inhibitor, and inhibitor dose. A recent discovery that may grant insight into this regulatory
mechanism is our laboratory’s detection of a specialized, neuron-specific proteasome bound to the plasma
membrane (NMP: neuronal membrane proteasome) that rapidly modulates activity-dependent neuronal calcium
signaling through the release of extracellular signaling peptides. Preliminary data from our laboratory has
demonstrated that NMP inhibition reduces dorsal root ganglion nociceptor activity and mechanical pain
sensitivity, indicating that this novel neuronal communication pathway may be critical in proteasome/pain
signaling. However, many fundamental questions about the NMP remain, including how it differs from cytosolic
proteasomes and how variable NMP expression across neuronal sub-populations affects pain sensation. The
central hypothesis of this proposal is that the PNS NMP plays an important role in pain signaling and that
characteristics of NMP expression in PNS sensory neurons, including subtype-specific activity patterns and
membrane localization patterns, directly affect its modulation of pain sensitization via differences in paracrine
signaling. To address this hypothesis, we propose a series of biochemical, molecular, physiological, and
behavioral assays addressing two specific aims: Aim 1. To determine the distribution and structure of the NMP
in PNS neuronal membranes; and Aim 2. To investigate the role of the PNS NMP in diverse neuronal subtypes
relevant to pain sensation. The completion of these aims will elucidate fundamental properties about the PNS
NMP and provide insight into its regulatory role in pain sensation, identifying possible therapeutic avenues for
pain modulation and laying the foundation for future investigations examining the role of the PNS NMP in health
and disease.

## Key facts

- **NIH application ID:** 11002264
- **Project number:** 5F31NS134239-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Taylor Renne Church
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11002264

## Citation

> US National Institutes of Health, RePORTER application 11002264, The Role of the Neuronal Membrane Proteasome in the Peripheral Nervous System and Pain Sensation (5F31NS134239-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11002264. Licensed CC0.

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