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Article

Calcium Increase and Substance P Release Induced by the Neurotoxin Brevetoxin-1 in Sensory Neurons: Involvement of PAR2 Activation through Both Cathepsin S and Canonical Signaling

1
EA4685 Laboratory of Interactions Neurons-Keratinocytes (LIEN), Faculty of Medicine and Health Sciences, University Brest, F-29200 Brest, France
2
Department of Dermatology, University Hospital of Brest, F-29200 Brest, France
3
InsermUMR1227, Lymphocytes B et Autoimmunity, University Brest, F-29200 Brest, France
4
Department of Dermatology and Allergology, Universitaetsmedizin Charit Berlin, D-10117 Berlin, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(12), 2704; https://doi.org/10.3390/cells9122704
Received: 27 November 2020 / Revised: 14 December 2020 / Accepted: 15 December 2020 / Published: 17 December 2020
(This article belongs to the Special Issue Pain, Itch and Sensory Nerve Endings)
Red tides involving Karenia brevis expose humans to brevetoxins (PbTxs). Oral exposition triggers neurotoxic shellfish poisoning, whereas inhalation induces a respiratory syndrome and sensory disturbances. No curative treatment is available and the pathophysiology is not fully elucidated. Protease-activated receptor 2 (PAR2), cathepsin S (Cat-S) and substance P (SP) release are crucial mediators of the sensory effects of ciguatoxins (CTXs) which are PbTx analogs. This work explored the role of PAR2 and Cat-S in PbTx-1-induced sensory effects and deciphered the signaling pathway involved. We performed calcium imaging, PAR2 immunolocalization and SP release experiments in monocultured sensory neurons or co-cultured with keratinocytes treated with PbTx-1 or P-CTX-2. We demonstrated that PbTx-1-induced calcium increase and SP release involved Cat-S, PAR2 and transient receptor potential vanilloid 4 (TRPV4). The PbTx-1-induced signaling pathway included protein kinase A (PKA) and TRPV4, which are compatible with the PAR2 biased signaling induced by Cat-S. Internalization of PAR2 and protein kinase C (PKC), inositol triphosphate receptor and TRPV4 activation evoked by PbTx-1 are compatible with the PAR2 canonical signaling. Our results suggest that PbTx-1-induced sensory disturbances involve the PAR2-TRPV4 pathway. We identified PAR2, Cat-S, PKA, and PKC that are involved in TRPV4 sensitization induced by PbTx-1 in sensory neurons. View Full-Text
Keywords: brevetoxin; ciguatoxin; sensory disorders; substance P; cathepsin S; PAR2; biased pathway; canonical pathway brevetoxin; ciguatoxin; sensory disorders; substance P; cathepsin S; PAR2; biased pathway; canonical pathway
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MDPI and ACS Style

Pierre, O.; Fouchard, M.; Buscaglia, P.; Le Goux, N.; Leschiera, R.; Mignen, O.; Fluhr, J.W.; Misery, L.; Le Garrec, R. Calcium Increase and Substance P Release Induced by the Neurotoxin Brevetoxin-1 in Sensory Neurons: Involvement of PAR2 Activation through Both Cathepsin S and Canonical Signaling. Cells 2020, 9, 2704. https://doi.org/10.3390/cells9122704

AMA Style

Pierre O, Fouchard M, Buscaglia P, Le Goux N, Leschiera R, Mignen O, Fluhr JW, Misery L, Le Garrec R. Calcium Increase and Substance P Release Induced by the Neurotoxin Brevetoxin-1 in Sensory Neurons: Involvement of PAR2 Activation through Both Cathepsin S and Canonical Signaling. Cells. 2020; 9(12):2704. https://doi.org/10.3390/cells9122704

Chicago/Turabian Style

Pierre, Ophélie, Maxime Fouchard, Paul Buscaglia, Nelig Le Goux, Raphaël Leschiera, Olivier Mignen, Joachim W. Fluhr, Laurent Misery, and Raphaële Le Garrec. 2020. "Calcium Increase and Substance P Release Induced by the Neurotoxin Brevetoxin-1 in Sensory Neurons: Involvement of PAR2 Activation through Both Cathepsin S and Canonical Signaling" Cells 9, no. 12: 2704. https://doi.org/10.3390/cells9122704

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