The nociceptive activity of peripheral sensory neurons is modulated by the neuronal membrane proteasome, 2024, Landeros et al.

[SNT Gatchaman]

The nociceptive activity of peripheral sensory neurons is modulated by the neuronal membrane proteasome
Eric Villalón Landeros; Samuel C. Kho; Taylor R. Church; Anna Brennan; Fulya Türker; Michael Delannoy; Michael J. Caterina; Seth S. Margolis

Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of the neuronal membrane proteasome (NMP). We show that specific inhibition of the NMP on distal nerve fibers innervating the mouse hind paw leads to reduction in mechanical and pain sensitivity. Through investigating PNS NMPs, we demonstrate their presence on the somata and proximal and distal axons of a subset of dorsal root ganglion (DRG) neurons.

Single-cell RNA sequencing experiments reveal that the NMP-expressing DRGs are primarily MrgprA3+ and Cysltr2+. NMP inhibition in DRG cultures leads to cell-autonomous and non-cell-autonomous changes in Ca2+ signaling induced by KCl depolarization, αβ-meATP, or the pruritogen histamine.

Taken together, these data support a model whereby NMPs are expressed on a subset of somatosensory DRGs to modulate signaling between neurons of distinct sensory modalities and indicate the NMP as a potential target for controlling pain.


Link | PDF (Cell Reports) [Open Access]

 

[SNT Gatchaman]

Proteasomes, which catalyze most of the protein degradation in all mammalian cells, are more complex than generally appreciated. Proteasomes exist as multi-subunit complexes in association with various regulatory particles to mediate ubiquitin-dependent and ubiquitin-independent protein degradation. Moreover, within neurons, proteasomes are localized throughout the cell from the nucleus to the cytosol, axons, dendrites, and synapses.

Our laboratory discovered a neuronal-specific proteasome complex in the central nervous system (CNS). This proteasome complex is tightly associated with the neuronal plasma membrane in a manner that allows for the degradation of intracellular neuronal proteins into signaling peptides that are released directly into the extracellular space. Remarkably, these extracellular peptides were determined to modulate the activity of naive CNS neurons, in part through N-methyl-D-aspartate receptor-dependent Ca2+ signaling. These data are extraordinary and reveal the NMP as a mediator of communication between neurons (inter-neuronal) important for modulating nervous system signaling.

In this study ,we revealed the presence and function of NMPs in the PNS. Anatomical and transcriptomic analysis showed that the NMP was not found on all DRG neurons, but rather was enriched almost exclusively (>95%) in two transcriptionally distinct populations of DRG neurons; MrgprA3 + and Cysltr2+ . MrgprA3 + and Cysltr2 + neurons are C-type nociceptors that overlap with IB4, CGRP, and NF-H, 94 are sensitive to mechanical and heat stimulation, respond to pruritogens such as histamine

Decades of studies aimed at understanding the mechanisms that control peripheral nociceptor activity have revealed that PNS sensory neurons are able to communicate with one another and that this ‘‘crosstalk,’’ to some extent, mediates a heightened sensitivity to stimuli resulting in neuropathic pain.