The Nociceptive Activity of Peripheral Sensory Neurons is Modulated by the Neuronal Membrane Proteasome

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. Investigating PNS NMPs we demonstrate their presence on the somata, 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, ab-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 Primary mouse DRG nuerons isolated from 21 - 30 day old C57Bl/6 mice. All DRGs from 4 mice were combined together for each sample. Antibody feeding on live cells was performed immediately after dissociation of cells to label neurons positive for the NMP. Cells were then FACS sorted to separate into NMP-positive and NMP-negative neurons. The cells were then submitted for single cell RNA-sequencing analyisis.