Highlights
- •PAR3 is broadly distributed in mouse DRGs and is co-expressed with other PARs.
- •Novel peptidomimetic compound 660 selectively activates PAR3.
- •Knocking out PAR3 potentiates the pronociceptive effects of PAR1 agonists.
- •PAR3 plays a crucial role in hyperalgesic priming.
Abstract
The protease activated receptor (PAR) family is a group of G-protein coupled receptors
(GPCRs) activated by proteolytic cleavage of the extracellular domain. PARs are expressed
in a variety of cell types with crucial roles in homeostasis, immune responses, inflammation,
and pain. PAR3 is the least researched of the four PARs, with little known about its
expression and function. We sought to better understand its potential function in
the peripheral sensory nervous system. Mouse single-cell RNA sequencing data demonstrates
that PAR3 is widely expressed in dorsal root ganglion (DRG) neurons. Co-expression
of PAR3 mRNA with other PARs was identified in various DRG neuron subpopulations,
consistent with its proposed role as a coreceptor of other PARs. We developed a lipid
tethered PAR3 agonist, C660, that selectively activates PAR3 by eliciting a Ca2+ response in DRG and trigeminal neurons. In vivo, C660 induces mechanical hypersensitivity and facial grimacing in WT but not PAR3−/− mice. We characterized other nociceptive phenotypes in PAR3−/− mice and found a loss of hyperalgesic priming in response to IL-6, carrageenan, and
a PAR2 agonist, suggesting that PAR3 contributes to long-lasting nociceptor plasticity
in some contexts. To examine the potential role of PAR3 in regulating the activity
of other PARs in sensory neurons, we administered PAR1, PAR2, and PAR4 agonists and
assessed mechanical and affective pain behaviors in WT and PAR3−/− mice. We observed that the nociceptive effects of PAR1 agonists were potentiated
in the absence of PAR3. Our findings suggest a complex role of PAR3 in the physiology
and plasticity of nociceptors.
Perspective
We evaluated the role of PAR3, a G-protein coupled receptor, in nociception by developing
a selective peptide agonist. Our findings suggest that PAR3 contributes to nociception
in various contexts and plays a role in modulating the activity of other PARs.
Graphical abstract
Graphical Abstract
Key Words
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Article info
Publication history
Published online: January 08, 2021
Accepted:
December 20,
2020
Received in revised form:
December 2,
2020
Received:
September 16,
2020
Footnotes
Conflicts of interest The authors declare no conflicts of interest.
This work was supported by NIH grants NS098826 (TJP, GD, SB, and JV), NS065926 (TJP), NS072204 (GD), and training grant NS096963 (SNH).
Identification
Copyright
© 2021 by United States Association for the Study of Pain, Inc.
