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 Acid-sensing ion channels in sensory signaling

2020 ◽  
Vol 318 (3) ◽  
pp. F531-F543 ◽  
Author(s):  
Marcelo D. Carattino ◽  
Nicolas Montalbetti
Keyword(s):  
Nervous System ◽  
Ion Channels ◽  
Peripheral Nervous System ◽  
Sensory Neurons ◽  
Genetically Modified ◽  
Physiological Processes ◽  
Acid Sensing Ion Channels ◽  
Genetically Modified Mice ◽  
Sensory Processes

Acid-sensing ion channels (ASICs) are cation-permeable channels that in the periphery are primarily expressed in sensory neurons that innervate tissues and organs. Soon after the cloning of the ASIC subunits, almost 20 yr ago, investigators began to use genetically modified mice to assess the role of these channels in physiological processes. These studies provide critical insights about the participation of ASICs in sensory processes, including mechanotransduction, chemoreception, and nociception. Here, we provide an extensive assessment of these findings and discuss the current gaps in knowledge with regard to the functions of ASICs in the peripheral nervous system.

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.

scholarly journals Targeting Mitochondrial Ion Channels to Fight Cancer

2018 ◽  
Vol 19 (7) ◽  
pp. 2060 ◽  
Author(s):  
Magdalena Bachmann ◽  
Roberto Costa ◽  
Roberta Peruzzo ◽  
Elena Prosdocimi ◽  
Vanessa Checchetto ◽  
...  
Keyword(s):  
Ion Channels ◽  
Tumor Development ◽  
Cancer Development ◽  
Cancer Growth ◽  
Altered Expression ◽  
New Frontier ◽  
Near Future

In recent years, several experimental evidences have underlined a new role of ion channels in cancer development and progression. In particular, mitochondrial ion channels are arising as new oncological targets, since it has been proved that most of them show an altered expression during tumor development and the pharmacological targeting of some of them have been demonstrated to be able to modulate cancer growth and progression, both in vitro as well as in vivo in pre-clinical mouse models. In this scenario, pharmacology of mitochondrial ion channels would be in the near future a new frontier for the treatment of tumors. In this review, we discuss the new advances in the field, by focusing our attention on the improvements in new drug developments to target mitochondrial ion channels.

scholarly journals Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy

2021 ◽  
Vol 118 (4) ◽  
pp. e2012685118
Author(s):  
Maria Elena Pero ◽  
Cristina Meregalli ◽  
Xiaoyi Qu ◽  
Grace Ji-eun Shin ◽  
Atul Kumar ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Pathogenic Role ◽  
Unmyelinated Fibers ◽  
Microtubule Stability ◽  
Altered Regulation

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.

scholarly journals Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy

2019 ◽  
Author(s):  
Maria Elena Pero ◽  
Cristina Meregalli ◽  
Xiaoyi Qu ◽  
Atul Kumar ◽  
Matthew Shorey ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Pathogenic Role ◽  
Pathogenic Mechanisms ◽  
Mitochondria Dynamics

ABSTRACTThe pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) is still poorly understood. Herein, we found that the CIPN-causing drug, bortezomib (Bort), induces delta 2 tubulin (D2) while affecting MT stability and dynamics in sensory neurons, and that accumulation of D2 is a hallmark of Bort-induced peripheral neuropathy in humans. Furthermore, while induction of D2 was sufficient to cause axonopathy and inhibit mitochondria motility, reducing D2 alleviated both axonal degeneration and loss of mitochondria motility promoted by Bort. Altogether, our data demonstrate that Bort, structurally unrelated to tubulin poisons, can affect the tubulin cytoskeleton in sensory neurons in vitro, in vivo and in humans, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. They further reveal a previously unrecognized pathogenic role for D2 in bortezomib-causing CIPN through its regulation of mitochondria dynamics.

scholarly journals Ion Channels in The Pathogenesis of Endometriosis: A Cutting-Edge Point of View

2020 ◽  
Vol 21 (3) ◽  
pp. 1114 ◽  
Author(s):  
Gaetano Riemma ◽  
Antonio Simone Laganà ◽  
Antonio Schiattarella ◽  
Simone Garzon ◽  
Luigi Cobellis ◽  
...  
Keyword(s):  
Ion Channels ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Urokinase Plasminogen Activator Receptor ◽  
Direct Role ◽  
Ectopic Endometrium

Background: Ion channels play a crucial role in many physiological processes. Several subtypes are expressed in the endometrium. Endometriosis is strictly correlated to estrogens and it is evident that expression and functionality of different ion channels are estrogen-dependent, fluctuating between the menstrual phases. However, their relationship with endometriosis is still unclear. Objective: To summarize the available literature data about the role of ion channels in the etiopathogenesis of endometriosis. Methods: A search on PubMed and Medline databases was performed from inception to November 2019. Results: Cystic fibrosis transmembrane conductance regulator (CFTR), transient receptor potentials (TRPs), aquaporins (AQPs), and chloride channel (ClC)-3 expression and activity were analyzed. CFTR expression changed during the menstrual phases and was enhanced in endometriosis samples; its overexpression promoted endometrial cell proliferation, migration, and invasion throughout nuclear factor kappa-light-chain-enhancer of activated B cells-urokinase plasminogen activator receptor (NFκB-uPAR) signaling pathway. No connection between TRPs and the pathogenesis of endometriosis was found. AQP5 activity was estrogen-increased and, through phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT), helped in vivo implantation of ectopic endometrium. In vitro, AQP9 participated in extracellular signal-regulated kinases/p38 mitogen-activated protein kinase (ERK/p38 MAPK) pathway and helped migration and invasion stimulating matrix metalloproteinase (MMP)2 and MMP9. ClC-3 was also overexpressed in ectopic endometrium and upregulated MMP9. Conclusion: Available evidence suggests a pivotal role of CFTR, AQPs, and ClC-3 in endometriosis etiopathogenesis. However, data obtained are not sufficient to establish a direct role of ion channels in the etiology of the disease. Further studies are needed to clarify this relationship.

scholarly journals Ciguatera fish poisoning and other seafood intoxication syndromes: A revisit and a review of the existing treatments employed in ciguatera fish poisoning

2010 ◽  
Vol 28 (1) ◽  
pp. 1 ◽  
Author(s):  
Shilpa Kumar-Roiné ◽  
Mariko Matsui ◽  
Serge Pauillac ◽  
Dominique Laurent
Keyword(s):  
Case Reports ◽  
Reef Fishes ◽  
Herbal Remedies ◽  
In Vitro Tests ◽  
Shellfish Poisoning ◽  
Ciguatera Fish Poisoning ◽  
Fish Poisoning ◽  
The Pacific

Ciguatera fish poisoning (CFP) is acquired through consumption of tropical reef fishes, contaminated with potent neurotoxins, ciguatoxins (CTXs), produced by benthic dinoflagellate of the Gambierdiscus genus. Both spatially and temporally unpredictable, a tainted fish is impossible to differentiate from an untainted one by appearance, taste, texture or odour. Given the predominance of reef fish in the diet of insular countries, the risk of CFP is ever-present. In the Pacific where the incidence of CFP is the highest, the consequences on public health and socio-economy can be extremely severe. Multidisciplinary in nature, the present review revisits the phenomenon of CFP, covering certain of its aspects, notably the etiology, toxicology, ecotoxicology, pharmacology, pathology and the treatments administrated. These aspects of CFP have been reviewed in relation to other poisoning syndromes: tetrodotoxin poisoning and other dinoflagellates- or diatoms-associated intoxications such as paralytic (PSP), diarrhetic (DSP), neurotoxic (NSP), amnesic (ASP) and azaspiracid shellfish poisoning (AZP) and palytoxin poisoning. Based on case reports and bibliographic accounts, a list inventorying the western medicines prescribed to patients suffering from CFP has been established. Within the last two decades, several of the herbal remedies have been evaluated for their efficiencies in in vivo and in a number of in vitro tests, which have also been reviewed herein.

scholarly journals Expression of recombinant myelin-associated glycoprotein in primary Schwann cells promotes the initial investment of axons by myelinating Schwann cells.

1990 ◽  
Vol 111 (3) ◽  
pp. 1171-1182 ◽  
Author(s):  
G C Owens ◽  
C J Boyd ◽  
R P Bunge ◽  
J L Salzer
Keyword(s):  
Schwann Cells ◽  
Sensory Neurons ◽  
Constitutive Expression ◽  
Integral Membrane Protein ◽  
Developmentally Regulated ◽  
Myelin Associated Glycoprotein ◽  
Normal Requirement

Myelin-associated glycoprotein (MAG) is an integral membrane protein expressed by myelinating glial cells that occurs in two developmentally regulated forms with different carboxyterminal cytoplasmic domains (L-MAG and S-MAG). To investigate the role of MAG in myelination a recombinant retrovirus was used to introduce a MAG cDNA (L-MAG form) into primary Schwann cells in vitro. Stably infected populations of cells were obtained that constitutively expressed MAG at the cell surface without the normal requirement for neuronal contact to induce expression. Constitutive expression of L-MAG did not affect myelination. In long term co-culture with purified sensory neurons, the higher level of MAG expression on infected Schwann cells was reduced to control levels on cells that formed myelin. On the other hand, unlike normal Schwann cells, infected Schwann cells associated with nonmyelinated axons or undergoing Wallerian degeneration expressed high levels of MAG. This suggests that a posttranscriptional mechanism modulates MAG expression during myelination. Immunostaining myelinating cultures with an antibody specific to L-MAG showed that L-MAG was normally transiently expressed at the earliest stages of myelination. In short term co-culture with sensory neurons, infected Schwann cells expressing only L-MAG segregated and ensheathed larger axons after 4 d in culture provided that an exogenous basal lamina was supplied. Similar activity was rarely displayed by control Schwann cells correlating with the low level of MAG induction after 4 d. These data strongly suggest that L-MAG promotes the initial investment by Schwann cells of axons destined to be myelinated.

Phenotypic characterization of gastric sensory neurons in mice

2006 ◽  
Vol 291 (5) ◽  
pp. G987-G997 ◽  
Author(s):  
Klaus Bielefeldt ◽  
Fang Zhong ◽  
H. Richard Koerber ◽  
Brian M. Davis
Keyword(s):  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Vagal Afferents ◽  
Phenotypic Characterization ◽  
Transient Receptor Potential Vanilloid ◽  
Mechanical Stimuli ◽  
Wide Range ◽  
Stimulation Of

Recent studies suggest that the capsaicin receptor [transient receptor potential vanilloid (TRPV)1] may play a role in visceral mechanosensation. To address the potential role of TRPV1 in vagal sensory neurons, we developed a new in vitro technique allowing us to determine TRPV1 expression directly in physiologically characterized gastric sensory neurons. Stomach, esophagus, and intact vagus nerve up to the central terminations were carefully dissected and placed in a perfusion chamber. Intracellular recordings were made from the soma of nodose neurons during mechanical stimulation of the stomach. Physiologically characterized neurons were labeled iontophoretically with neurobiotin and processed for immunohistochemical experiments. As shown by action potential responses triggered by stimulation of the upper thoracic vagus with a suction electrode, essentially all abdominal vagal afferents in mice conduct in the C-fiber range. Mechanosensitive gastric afferents encode stimulus intensities over a wide range without apparent saturation when punctate stimuli are used. Nine of 37 mechanosensitive vagal afferents expressed TRPV1 immunoreactivity, with 8 of the TRPV1-positive cells responding to stretch. A small number of mechanosensitive gastric vagal afferents express neurofilament heavy chains and did not respond to stretch. By maintaining the structural and functional integrity of vagal afferents up to the nodose ganglion, physiological and immunohistochemical properties of mechanosensory gastric sensory neurons can be studied in vitro. Using this novel technique, we identified TRPV1 immunoreactivity in only one-fourth of gastric mechanosensitive neurons, arguing against a major role of this ion channel in sensation of mechanical stimuli under physiological conditions.

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