The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell–derived sensory neurons of erythromelalgia patients

Meents, Jannis; Bressan, Elisângela; Sontag, Stephanie; Foerster, Alec; Hautvast, Petra; Rösseler, Corinna; Hampl, Martin; Schüler, H; Goetzke, Roman; Le, Thi Kim Chi; Kleggetveit, Inge Petter; Cann, Kim Le; Kerth, Clara M.; Rush, Anthony M.; Rogers, Marc; Kohl, Zacharias; Schmelz, Martin; Wagner, Wolfgang; Jørum, Ellen; Namer, Barbara; Winner, Beate; Zenke, Martin; Lampert, Angelika

doi:10.1097/j.pain.0000000000001511

Cited by 79 publications

(90 citation statements)

References 48 publications

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“…However, the functional excitability profile of the generated neurons must be investigated to provide a reliable functional baseline for the model's applicability in the investigation of diseases or the effect of drugs on defined ion channels. Functional profiling of hPSC-derived sensory neurons has primarily been focused on protocols that generate nociceptors (Chambers et al, 2012;Young et al, 2014;Blanchard et al, 2015;Eberhardt et al, 2015;Wainger et al, 2015;McDermott et al, 2019;Meents et al, 2019;Schoepf et al, 2020), rather than a heterogeneous population of sensory neurons akin to a more physiologically relevant model in which diverse populations of sensory neurons coexist. In this study, we sought to profile the spontaneously resulting mixed population of DRG sensory neurons at the transcriptional and functional levels including a detailed description of NGN2 iSN excitability patterns and their underlying voltage-dependent conductances.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Characterization of Neurogenin-2 Induced Human Sensory Neurons

Hulme

McArthur

Maksour

et al. 2020

Front. Cell. Neurosci.

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Sensory perception is fundamental to everyday life, yet understanding of human sensory physiology at the molecular level is hindered due to constraints on tissue availability. Emerging strategies to study and characterize peripheral neuropathies in vitro involve the use of human pluripotent stem cells (hPSCs) differentiated into dorsal root ganglion (DRG) sensory neurons. However, neuronal functionality and maturity are limited and underexplored. A recent and promising approach for directing hPSC differentiation towards functionally mature neurons involves the exogenous expression of Neurogenin-2 (NGN2). The optimized protocol described here generates sensory neurons from hPSC-derived neural crest (NC) progenitors through virally induced NGN2 expression. NC cells were derived from hPSCs via a small molecule inhibitor approach and enriched for migrating NC cells (66% SOX10+ cells). At the protein and transcript level, the resulting NGN2 induced sensory neurons (NGN2iSNs) express sensory neuron markers such as BRN3A (82% BRN3A+ cells), ISLET1 (91% ISLET1+ cells), TRKA, TRKB, and TRKC. Importantly, NGN2iSNs repetitively fire action potentials (APs) supported by voltage-gated sodium, potassium, and calcium conductances. In-depth analysis of the molecular basis of NGN2iSN excitability revealed functional expression of ion channels associated with the excitability of primary afferent neurons, such as Nav1.7, Nav1.8, Kv1.2, Kv2.1, BK, Cav2.1, Cav2.2, Cav3.2, ASICs and HCN among other ion channels, for which we provide functional and transcriptional evidence. Our characterization of stem cell-derived sensory neurons sheds light on the molecular basis of human sensory physiology and highlights the suitability of using hPSC-derived sensory neurons for modeling human DRG development and their potential in the study of human peripheral neuropathies and drug therapies.

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Section: Discussionmentioning

confidence: 99%

Molecular and Functional Characterization of Neurogenin-2 Induced Human Sensory Neurons

Hulme

McArthur

Maksour

et al. 2020

Front. Cell. Neurosci.

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“…Nav1.7 is an important element of VGSC expression in peripheral nerves. In an inflammatory pain mouse model, the knockout of Nav1.7 revealed deficits in behavioral studies [7]. Nav1.7 in nociceptors plays a central role in skeletal muscle nociceptive sensitization [8].…”

Section: Introductionmentioning

confidence: 99%

Nav1.7 via Promotion of ERK in the Trigeminal Ganglion Plays an Important Role in the Induction of Pulpitis Inflammatory Pain

Sun

Jiang

et al. 2019

BioMed Research International

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The trigeminal ganglion (TG) refers to sensory neurons bodies that innervate the spinal cord and peripheral axons that innervate teeth. The tetrodotoxin-sensitive sodium (NA) channels (Nav1.7) play important roles in the pathophysiology of pain. In this study, we investigated the TG expression of Nav1.7 and extracellular signal-regulated kinase (ERK) in a rat model of pulpitis to explore the correlation between these channels and inflammatory pain. Pulpitis was confirmed by hematoxylin-eosin staining. In this study, we demonstrated that the reflex of rats to mechanical stimulation increases after pulp exposure and that the exposed rat molar pulp can upregulate the expression of Nav1.7 and ERK in the rat TG. Three days after rat pulp exposure, the expression levels of the two ion channels in the TG increased. TG target injection of PF04856264, a Nav1.7 inhibitor, dose-dependently increased the mechanical pain threshold and was able to inhibit ERK expression. TG target injection of PD98059, an ERK inhibitor, dose-dependently increased the mechanical pain threshold. These factors simultaneously resulted in the highest production. In this study, with the established link to inflammatory pain, we found that Nav1.7 and ERK both play important roles in the induction of inflammatory pain caused by pulpitis. We also found a correlation between the expression levels of Nav1.7 and ERK and the degree of inflammatory pain. Furthermore, ERK signaling pathways were promoted by the Nav1.7 in TG after pulpitis.

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“…In other ion channels, such as transient receptor potential and potassium channels, different forms of hysteresis have been described, including an increase in conduction or sensitivity upon prolonged or repeated stimulation (see below and in Reference [32]. However, our group has failed to show changes in voltage dependence of activation of Nav1.7 after a series of depolarizing pre-pulses, thus questioning the role of positive hysteresis in Nav1.7 [33].…”

Section: Sodium Channelsmentioning

confidence: 99%

Noncanonical Ion Channel Behaviour in Pain

Ciotu

Tsantoulas

Meents

et al. 2019

IJMS

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Ion channels contribute fundamental properties to cell membranes. Although highly diverse in conductivity, structure, location, and function, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Primarily considering ion channels involved in the nociceptive system, this review covers more novel and less known features. Accordingly, we outline noncanonical operation of voltage-gated sodium, potassium, transient receptor potential (TRP), and hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Noncanonical features discussed include properties as a memory for prior voltage and chemical exposure, alternative ion conduction pathways, cluster formation, and silent subunits. Complementary to this main focus, the intention is also to transfer knowledge between fields, which become inevitably more separate due to their size.

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The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell–derived sensory neurons of erythromelalgia patients

Abstract: Supplemental Digital Content is Available in the Text. Human sodium channel Na V 1.7 in induced pluripotent stem cell–derived sensory neurons sets the action potential threshold but does not support subthreshold depolarizations.

Cited by 79 publications

References 48 publications

Molecular and Functional Characterization of Neurogenin-2 Induced Human Sensory Neurons

Molecular and Functional Characterization of Neurogenin-2 Induced Human Sensory Neurons

Nav1.7 via Promotion of ERK in the Trigeminal Ganglion Plays an Important Role in the Induction of Pulpitis Inflammatory Pain

Noncanonical Ion Channel Behaviour in Pain

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