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

Pierre, Ophélie; Fouchard, Maxime; Buscaglia, Paul; Le Goux, Nelig; Leschiera, Raphaël; Mignen, Olivier; Fluhr, Joachim W.; Misery, Laurent; Le Garrec, Raphaële

doi:10.3390/cells9122704

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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

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Raphaële Le Garrec

EA4685 Laboratory of Interactions Neurons-Keratinocytes (LIEN), Faculty of Medicine and Health Sciences, University Brest, F-29200 Brest, France

Department of Dermatology, University Hospital of Brest, F-29200 Brest, France

InsermUMR1227, Lymphocytes B et Autoimmunity, University Brest, F-29200 Brest, France

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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)

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Abstract

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

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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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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

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