scholarly journals 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 ◽  
Vol 9 (12) ◽  
pp. 2704
Author(s):  
Ophélie Pierre ◽  
Maxime Fouchard ◽  
Paul Buscaglia ◽  
Nelig Le Goux ◽  
Raphaël Leschiera ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Substance P ◽  
Signaling Pathway ◽  
Sensory Neurons ◽  
Cathepsin S ◽  
Transient Receptor Potential Vanilloid ◽  
Red Tides ◽  
Shellfish Poisoning ◽  
Sensory Effects ◽  
Sensory Disturbances

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.

Activation of bitter taste receptors in pulmonary nociceptors sensitizes TRPV1 channels through the PLC and PKC signaling pathway

2017 ◽  
Vol 312 (3) ◽  
pp. L326-L333 ◽  
Author(s):  
Qihai (David) Gu ◽  
Deanna S. Joe ◽  
Carolyn A. Gilbert
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Signaling Pathway ◽  
Sensory Neurons ◽  
Bitter Taste ◽  
Right Atrial ◽  
Taste Receptors ◽  
Kinase C ◽  
Bitter Taste Receptors

Bitter taste receptors (T2Rs), a G protein-coupled receptor family capable of detecting numerous bitter-tasting compounds, have recently been shown to be expressed and play diverse roles in many extraoral tissues. Here we report the functional expression of T2Rs in rat pulmonary sensory neurons. In anesthetized spontaneously breathing rats, intratracheal instillation of T2R agonist chloroquine (10 mM, 0.1 ml) significantly augmented chemoreflexes evoked by right-atrial injection of capsaicin, a specific activator for transient receptor potential vanilloid receptor 1 (TRPV1), whereas intravenous infusion of chloroquine failed to significantly affect capsaicin-evoked reflexes. In patch-clamp recordings with isolated rat vagal pulmonary sensory neurons, pretreatment with chloroquine (1−1,000 µM, 90 s) concentration dependently potentiated capsaicin-induced TRPV1-mediated inward currents. Preincubating with diphenitol and denatonium (1 mM, 90 s), two other T2R activators, also enhanced capsaicin currents in these neurons but to a lesser extent. The sensitizing effect of chloroquine was effectively prevented by the phospholipase C inhibitor U73122 (1 µM) or by the protein kinase C inhibitor chelerythrine (10 µM). In summary, our study showed that activation of T2Rs augments capsaicin-evoked TRPV1 responses in rat pulmonary nociceptors through the phospholipase C and protein kinase C signaling pathway.

scholarly journals Resolvin E1 Inhibits Substance P-Induced Potentiation of TRPV1 in Primary Sensory Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Youn Yi Jo ◽  
Ji Yeon Lee ◽  
Chul-Kyu Park
Keyword(s):  
Substance P ◽  
G Protein ◽  
Sensory Neurons ◽  
Inflammatory Pain ◽  
Dorsal Root Ganglion Neurons ◽  
Peripheral Inflammation ◽  
Transient Receptor Potential Vanilloid ◽  
Primary Sensory Neurons ◽  
Nociceptive Neurons ◽  
Ganglion Neurons

The neuropeptide substance P (SP) is expressed in primary sensory neurons and is commonly regarded as a “pain” neurotransmitter. Upon peripheral inflammation, SP activates the neurokinin-1 (NK-1) receptor and potentiates activity of transient receptor potential vanilloid subtype 1 (TRPV1), which is coexpressed by nociceptive neurons. Therefore, SP functions as an important neurotransmitter involved in the hypersensitization of inflammatory pain. Resolvin E1 (RvE1), derived from omega-3 polyunsaturated fatty acids, inhibits TRPV1 activity via activation of the chemerin 23 receptor (ChemR23)—an RvE1 receptor located in dorsal root ganglion neurons—and therefore exerts an inhibitory effect on inflammatory pain. We demonstrate here that RvE1 regulates the SP-induced potentiation of TRPV1 via G-protein coupled receptor (GPCR) on peripheral nociceptive neurons. SP-induced potentiation of TRPV1 inhibited by RvE1 was blocked by the Gαi-coupled GPCR inhibitor pertussis toxin and the G-protein inhibitor GDPβ-S. These results indicate that a low concentration of RvE1 strongly inhibits the potentiation of TRPV1, induced by the SP-mediated activation of NK-1, via a GPCR signaling pathway activated by ChemR23 in nociceptive neurons. RvE1 might represent a new therapeutic target for the treatment of inflammatory pain as a prospective endogenous inhibitor that strongly inhibits TRPV1 activity associated with peripheral inflammation.

scholarly journals Pacific-Ciguatoxin-2 and Brevetoxin-1 Induce the Sensitization of Sensory Receptors Mediating Pain and Pruritus in Sensory Neurons

Marine Drugs ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. 387
Author(s):  
Ophélie Pierre ◽  
Maxime Fouchard ◽  
Nelig Le Goux ◽  
Paul Buscaglia ◽  
Raphaël Leschiera ◽  
...  
Keyword(s):  
Ion Channels ◽  
Sensory Neurons ◽  
Sensory Receptors ◽  
Shellfish Poisoning ◽  
Fish Poisoning ◽  
Intense Pruritus ◽  
Sensory Disturbances ◽  
Nav Channels

Ciguatera fish poisoning (CFP) and neurotoxic shellfish poisoning syndromes are induced by the consumption of seafood contaminated by ciguatoxins and brevetoxins. Both toxins cause sensory symptoms such as paresthesia, cold dysesthesia and painful disorders. An intense pruritus, which may become chronic, occurs also in CFP. No curative treatment is available and the pathophysiology is not fully elucidated. Here we conducted single-cell calcium video-imaging experiments in sensory neurons from newborn rats to study in vitro the ability of Pacific-ciguatoxin-2 (P-CTX-2) and brevetoxin-1 (PbTx-1) to sensitize receptors and ion channels, (i.e., to increase the percentage of responding cells and/or the response amplitude to their pharmacological agonists). In addition, we studied the neurotrophin release in sensory neurons co-cultured with keratinocytes after exposure to P-CTX-2. Our results show that P-CTX-2 induced the sensitization of TRPA1, TRPV4, PAR2, MrgprC, MrgprA and TTX-r NaV channels in sensory neurons. P-CTX-2 increased the release of nerve growth factor and brain-derived neurotrophic factor in the co-culture supernatant, suggesting that those neurotrophins could contribute to the sensitization of the aforementioned receptors and channels. Our results suggest the potential role of sensitization of sensory receptors/ion channels in the induction or persistence of sensory disturbances in CFP syndrome.

scholarly journals Rutaecarpine Increases Nitric Oxide Synthesis via eNOS Phosphorylation by TRPV1-Dependent CaMKII and CaMKKβ/AMPK Signaling Pathway in Human Endothelial Cells

2021 ◽  
Vol 22 (17) ◽  
pp. 9407
Author(s):  
Gi Ho Lee ◽  
Chae Yeon Kim ◽  
Chuanfeng Zheng ◽  
Sun Woo Jin ◽  
Ji Yeon Kim ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Ampk Signaling ◽  
Compound C ◽  
Enos Phosphorylation

Rutaecarpine (RUT) is a bioactive alkaloid isolated from the fruit of Evodia rutaecarpa that exerts a cellular protective effect. However, its protective effects on endothelial cells and its mechanism of action are still unclear. In this study, we demonstrated the effects of RUT on nitric oxide (NO) synthesis via endothelial nitric oxide synthase (eNOS) phosphorylation in endothelial cells and the underlying molecular mechanisms. RUT treatment promoted NO generation by increasing eNOS phosphorylation. Additionally, RUT induced an increase in intracellular Ca2+ concentration and phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), and Ca2+/calmodulin-dependent kinase II (CaMKII). Inhibition of transient receptor potential vanilloid type 1 (TRPV1) attenuated RUT-induced intracellular Ca2+ concentration and phosphorylation of CaMKII, CaMKKβ, AMPK, and eNOS. Treatment with KN-62 (a CaMKII inhibitor), Compound C (an AMPK inhibitor), and STO-609 (a CaMKKβ inhibitor) suppressed RUT-induced eNOS phosphorylation and NO generation. Interestingly, RUT attenuated the expression of ICAM-1 and VCAM-1 induced by TNF-α and inhibited the inflammation-related NF-κB signaling pathway. Taken together, these results suggest that RUT promotes NO synthesis and eNOS phosphorylation via the Ca2+/CaMKII and CaM/CaMKKβ/AMPK signaling pathways through TRPV1. These findings provide evidence that RUT prevents endothelial dysfunction and benefit cardiovascular health.

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