scholarly journals Nav1.7 gating in human iPSC derived sensory neurons: an experimental and computational study

2020 ◽  
Author(s):  
Alberto Capurro ◽  
Jack Thornton ◽  
Bruno Cessac ◽  
Lyle Armstrong ◽  
Evelyne Sernagor
Keyword(s):  
Sensory Neurons ◽  
Computational Study ◽  
Critical Role ◽  
Computational Modelling ◽  
Electrode Array ◽  
Receptor Potential ◽  
Nociceptive Neurons ◽  
Inactivation Gating ◽  
Induced Pluripotent

AbstractChronic pain is a global healthcare problem with a huge societal impact. Its management remains unsatisfactory, with no single treatment clinically approved in most cases. In this study we use an in vitro experimental model of erythromelalgia consisting of sensory neurons derived from human induced pluripotent stem cells obtained from a patient (carrying the mutation F1449V) and a control subject. We combine neurophysiology and computational modelling to focus on the Nav1.7 voltage gated sodium channel, which acts as an amplifier of the receptor potential in nociceptive neurons and plays a critical role in erythromelalgia due to gain of function mutations causing the channel to open with smaller depolarisations.Using multi-electrode array (extracellular) recordings, we found that the scorpion toxin OD1 increases the excitability of sensory neurons in cultures obtained from the control donor, evidenced by increased spontaneous spike rate and amplitude. In erythromelalgia cultures, the application of the Nav1.7 blocker PF-05089771 effectively stopped spontaneous firing. These results, which are in accordance with current clamp and voltage clamp recordings reported in the literature, are explained with a conductance-based computational model of a single human nociceptive neuron. The disease was simulated through a decrease of the Nav1.7 half activation voltage, which decreased the rheobase and increased the response to supra threshold depolarizing currents. This enhanced response could be successfully supressed by blocking the Nav1.7 channels. The painful effects of OD1 were simulated through a slower establishment and a quicker removal of Nav1.7 inactivation, reproducing the effects of the toxin on the spike frequency and amplitude. Our model simulations suggest that the increase in extracellular spike amplitude observed in the MEA after OD1 treatment can be due mainly to a slope increase in the ascending phase of the intracellular spike caused by impaired inactivation gating.

scholarly journals Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 668
Author(s):  
Concetta Altamura ◽  
Maria Raffaella Greco ◽  
Maria Rosaria Carratù ◽  
Rosa Angela Cardone ◽  
Jean-François Desaphy
Keyword(s):  
Ovarian Cancer ◽  
Ion Channels ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Gynecologic Cancer ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Platinum Resistance

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia

2008 ◽  
Vol 294 (5) ◽  
pp. G1288-G1298 ◽  
Author(s):  
Walter E. B. Sipe ◽  
Stuart M. Brierley ◽  
Christopher M. Martin ◽  
Benjamin D. Phillis ◽  
Francisco Bautista Cruz ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Action Potentials ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mechanical Hyperalgesia ◽  
Transient Receptor Potential Vanilloid ◽  
Afferent Neurons ◽  
Nociceptive Neurons ◽  
Afferent Fibers ◽  
Transient Receptor

Protease-activated receptor (PAR2) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR2 cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR2-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR2, and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4+/+ mice, intraluminal PAR2 activating peptide (PAR2-AP) exacerbated VMR to graded CRD from 6–24 h, indicative of mechanical hyperalgesia. PAR2-induced hyperalgesia was not observed in TRPV4−/− mice. PAR2-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4+/+ mice, but not from TRPV4−/− mice. The TRPV4 agonists 5′,6′-epoxyeicosatrienoic acid and 4α-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR2-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR2 increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR2-induced mechanical hyperalgesia and excitation of colonic afferent neurons.

The link between an Nav1.7 mutation and erythromelalgia

2018 ◽  
Author(s):  
Bradley J. Kerr
Keyword(s):  
Sensory Neurons ◽  
Novel Mutation ◽  
Critical Role ◽  
Channel Blockers ◽  
Chronic Pain Condition ◽  
Nociceptive Neurons ◽  
Burning Pain ◽  
Voltage Dependent ◽  
Restricted Pattern

The landmark paper discussed in this chapter is ‘Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons’, published by Dib-Hajj et al. in 2005. The voltage-dependent sodium channels Nav1.7, Nav1.8, and Nav1.9 have a restricted pattern of expression in sensory neurons in the periphery and are concentrated in small nociceptive neurons of the dorsal root ganglion, the trigeminal ganglion, and the nodose ganglion. In this paper, Dib-Hajj and colleagues studied a family with erythromelalgia (Weir Mitchell disease), an autosomal-dominant, inherited pain disorder in which burning pain in the extremities can be triggered by warming of the skin or moderate exertion. By identifying a novel mutation in SCN9A, which encodes Nav1.7, they established the critical role of this specific ion channel in this patient population. These findings represent an important first step towards developing isoform-specific channel blockers for the treatment of an inherited chronic pain condition.

scholarly journals TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Yahui Zhang ◽  
Baohua Hou ◽  
Peiyu Liang ◽  
Xin Lu ◽  
Yifan Wu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Transient Receptor Potential ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Inflammasome Activation ◽  
Trpv1 Channel ◽  
Nlrp3 Inflammasome Activation

AbstractMultiple sclerosis (MS) is a chronic inflammatory autoimmune disease in the central nervous system (CNS). The NLRP3 inflammasome is considered an important regulator of immunity and inflammation, both of which play a critical role in MS. However, the underlying mechanism of NLRP3 inflammasome activation is not fully understood. Here we identified that the TRPV1 (transient receptor potential vanilloid type 1) channel in microglia, as a Ca2+ influx-regulating channel, played an important role in NLRP3 inflammasome activation. Deletion or pharmacological blockade of TRPV1 inhibited NLRP3 inflammasome activation in microglia in vitro. Further research revealed that TRPV1 channel regulated ATP-induced NLRP3 inflammasome activation through mediating Ca2+ influx and phosphorylation of phosphatase PP2A in microglia. In addition, TRPV1 deletion could alleviate mice experimental autoimmune encephalomyelitis (EAE) and reduce neuroinflammation by inhibiting NLRP3 inflammasome activation. These data suggested that the TRPV1 channel in microglia can regulate NLRP3 inflammasome activation and consequently mediate neuroinflammation. Meanwhile, our study indicated that TRPV1–Ca2+–PP2A pathway may be a novel regulator of NLRP3 inflammasome activation, pointing to TRPV1 as a potential target for CNS inflammatory diseases.

TRPV4 Is Required for Hypoxic Pulmonary Vasoconstriction

2015 ◽  
Vol 122 (6) ◽  
pp. 1338-1348 ◽  
Author(s):  
Neil M. Goldenberg ◽  
Liming Wang ◽  
Hannes Ranke ◽  
Wolfgang Liedtke ◽  
Arata Tabuchi ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Intravital Microscopy ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Critical Role ◽  
Receptor Potential ◽  
Epoxyeicosatrienoic Acid ◽  
Pulmonary Vasoconstriction

Abstract Background: Hypoxic pulmonary vasoconstriction (HPV) is critically important in regionally heterogeneous lung diseases by directing blood toward better-oxygenated lung units, yet the molecular mechanism of HPV remains unknown. Transient receptor potential (TRP) channels are a large cation channel family that has been implicated in HPV, specifically in the pulmonary artery smooth muscle cell (PASMC) Ca2+ and contractile response to hypoxia. In this study, the authors probed the role of the TRP family member, TRPV4, in HPV. Methods: HPV was assessed by using isolated perfused mouse lungs or by intravital microscopy to directly visualize pulmonary arterioles in mice. In vitro experiments were performed in primary human PASMC. Results: The hypoxia-induced pulmonary artery pressure increase seen in wild-type mice (5.6 ± 0.6 mmHg; mean ± SEM) was attenuated both by inhibition of TRPV4 (2.8 ± 0.5 mmHg), or in lungs from TRPV4-deficient mice (Trpv4−/−) (3.4 ± 0.5 mmHg; n = 7 each). Functionally, Trpv4−/− mice displayed an exaggerated hypoxemia after regional airway occlusion (pao2 71% of baseline ± 2 vs. 85 ± 2%; n = 5). Direct visualization of pulmonary arterioles by intravital microscopy revealed a 66% reduction in HPV in Trpv4−/− mice. In human PASMC, inhibition of TRPV4 blocked the hypoxia-induced Ca2+ influx and myosin light chain phosphorylation. TRPV4 may form a heteromeric channel with TRPC6 as the two channels coimmunoprecipitate from PASMC and as there is no additive effect of TRPC and TRPV4 inhibition on Ca2+ influx in response to the agonist, 11,12-epoxyeicosatrienoic acid. Conclusion: TRPV4 plays a critical role in HPV, potentially via cooperation with TRPC6.

scholarly journals Tropomyosin 1 genetically constrains in vitro hematopoiesis

2019 ◽  
Author(s):  
CS Thom ◽  
CD Jobaliya ◽  
K Lorenz ◽  
JA Maguire ◽  
A Gagne ◽  
...  
Keyword(s):  
Human Genetics ◽  
Computational Modelling ◽  
Erythroid Cell ◽  
Data Sets ◽  
Genome Wide ◽  
Causal Genes ◽  
Causal Variants ◽  
Association Data ◽  
Induced Pluripotent

AbstractIdentifying causal variants and genes from human genetics studies of hematopoietic traits are important to enumerate basic regulatory mechanisms underlying these traits, and could ultimately augment translational efforts to generate platelets and/or red blood cells in vitro. To identify putative causal genes from these data, we performed computational modelling using available genome-wide association data sets for platelet traits. Our model identified a joint collection of genomic features enriched at established platelet trait associations and plausible candidate variants. Additional studies associating variation at these loci with change in gene expression highlighted the Tropomyosin 1 (TPM1) among our top-ranked candidate genes. CRISPR/Cas9-mediated TPM1 knockout in human induced pluripotent stem cells (iPSCs) enhanced hematopoietic progenitor development, increasing total megakaryocyte as well as erythroid cell yields. Our findings may help explain human genetics associations and identify a novel genetic strategy to enhance in vitro hematopoiesis.

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