Endogenous Mas‐related G‐protein‐coupled receptor X1 activates and sensitizes TRPA1 in a human model of peripheral nerves

McMillan, Hayley; Lundy, Fionnuala T.; Dunne, Orla M.; Al-Natour, Banan; Jeanneau, Charlotte; About, Imad; Curtis, Tim M.; Karim, Ikhlas El

doi:10.1096/fj.202001667rr

Cited by 9 publications

(7 citation statements)

References 58 publications

(351 reference statements)

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“…We could recently show in monkey that polymodal C-fibers are the class of afferents primarily activated by the MRGPRX1 agonist BAM8–22 8 . Therefore, Aδ-fibers might underlie sensitization of cowhage-induced itch, but it remains unclear whether dermal Aδ-fibers in humans do also express MRGPRX1 receptors as shown for human dental pulp nociceptors 56 . Considering that polymodal C-fibers are sensitized by NGF, it is additionally surprising that volunteers did not report increased itch after BAM8–22 injection.…”

Section: Discussionmentioning

confidence: 99%

Microinjection of pruritogens in NGF-sensitized human skin

Solinski

Rukwied

Schmelz

2021

Sci Rep

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Single intradermal injections of nerve growth factor (NGF) evoke prolonged but temporally distinct sensitization patterns to somatosensory stimuli. Focal administration of the non-histaminergic pruritogen cowhage but not histamine resulted in elevated itch at day 21 after NGF administration. Here, we injected bovine adrenal medulla peptide 8–22 (BAM8–22), β-alanine (β-ALA) and endothelin-1 (ET-1) into NGF-treated skin of 11 healthy volunteers and investigated the corresponding itch/pain and flare reactions. β-ALA was the weakest pruritogen, while BAM8–22 and ET-1 were equally potent as histamine. NGF did not sensitize itch or flare reactions induced by any compound, but injection and evoked pain were increased at day 21 and 49. The involvement of histamine H1 receptors in itch was explored in eight subjects after oral cetirizine. ET-1-induced itch and flare were significantly reduced. BAM8–22 and β-ALA itch were not affected, but flare responses after BAM8–22 reduced by 50%. The results indicate that a single NGF injection does not sensitize for experimentally induced itch but increases pain upon pruritogen injection. In healthy humans, pruritic and algetic processing appear differentially regulated by NGF. However, in patients suffering chronic itch, prolonged elevation of NGF-levels under inflammatory conditions may contribute to elevated itch.

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Section: Discussionmentioning

confidence: 99%

Microinjection of pruritogens in NGF-sensitized human skin

Solinski

Rukwied

Schmelz

2021

Sci Rep

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“…Because membrane depolarization is evoked at synaptic sites, the excitability of neurons may be altered in neurons derived from PWS patients. Therefore, we analyzed the membrane potential in depolarized neuronal cells 30 . Membrane potential responses were measured using FluoVolt under the presence of high K + solution.…”

Section: Resultsmentioning

confidence: 99%

Defects in early synaptic formation and neuronal function in Prader-Willi syndrome

Soeda,

Ito,

Ogushi

et al. 2023

Sci Rep

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Prader-Willi syndrome (PWS), which is a complex epigenetic disorder caused by the deficiency of paternally expressed genes in chromosome 15q11-q13, is associated with several psychiatric dimensions, including autism spectrum disorder. We have previously reported that iPS cells derived from PWS patients exhibited aberrant differentiation and transcriptomic dysregulation in differentiated neural stem cells (NSCs) and neurons. Here, we identified SLITRK1 as a downregulated gene in NSCs differentiated from PWS patient iPS cells by RNA sequencing analysis. Because SLITRK1 is involved in synaptogenesis, we focused on the synaptic formation and function of neurons differentiated from PWS patient iPS cells and NDN or MAGEL2 single gene defect mutant iPS cells. Although βIII tubulin expression levels in all the neurons were comparable to the level of differentiation in the control, pre- and postsynaptic markers were significantly lower in PWS and mutant neurons than in control neurons. PSD-95 puncta along βIII tubulin neurites were also decreased. Membrane potential responses were measured while exposed to high K+ stimulation. The neuronal excitabilities in PWS and mutant neurons showed significantly lower intensity than that of control neurons. These functional defects in PWS neurons may reflect phenotypes of neurodevelopmental disorders in PWS.

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“…Membrane potential was measured as previously described (McMillan et al., 2021). Briefly, PSA‐NCAM+ and d‐PSA‐NCAM+ cells were loaded with FluoVolt™ loading solution (100X PowerLoad™ concentrate and FluoVolt™ dye, 1000X) (Invitrogen), in normal Hanks' solution for 20 min at room temperature, as recommended by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

Immunological isolation and characterization of neuronal progenitors from human dental pulp: A laboratory‐based investigation

McMillan,

Lundy,

Dunne

et al. 2024

Int Endodontic J

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AimsDental pulp stem cells (DPSCs) contain a population of stem cells with a broad range of differentiation potentials, as well as more lineage‐committed progenitors. Such heterogeneity is a significant obstacle to experimental and clinical applications. The aim of this study is to isolate and characterize a homogenous neuronal progenitor cell population from human DPSCs.MethodologyPolysialylated‐neural cell adhesion molecule (PSA‐NCAM+) neural progenitors were isolated from the dental pulp of three independent donors using magnetic‐activated cell sorting (MACS) technology. Immunofluorescent staining with a panel of neural and non‐neural markers was used to characterize the magnetically isolated PSA‐NCAM+ fraction. PSA‐NCAM+ cells were then cultured in Neurobasal A supplemented with neurotrophic factors: dibutyryl cyclic‐AMP, neurotrophin‐3, B27 and N2 supplements to induce neuronal differentiation. Both PSA‐NCAM+ and differentiated PSA‐NCAM+ cells were used in Ca2+ imaging studies to assess the functionality of P2X3 receptors as well as membrane depolarization.ResultsPSA‐NCAM+ neural progenitors were isolated from a heterogeneous population of hDPSCs using magnetic‐activated cell sorting and anti‐PSA‐NCAM MicroBeads. Flow cytometry analysis demonstrated that immunomagnetic sorting significantly increased the purity of PSA‐NCAM+ cells. Immunofluorescent staining revealed expression of pan‐neuronal and mature neuronal markers, PGP9.5 and MAP2, respectively, as well as weak expression of the mature sensory markers, peripherin and islet1. ATP‐induced response was mediated predominately by P2X3 receptors in both undifferentiated and differentiated cells, with a greater magnitude observed in the latter. In addition, membrane depolarizations were also detected in cells before and after differentiation when loaded with fast‐voltage‐responding fluorescent molecule, FluoVolt™ in response to potassium chloride. Interestingly, only differentiated PSA‐NCAM+ cells were capable of spontaneous membrane oscillations.ConclusionsIn summary, DPSCs contain a population of neuronal progenitors with enhanced neural differentiation and functional neural‐like properties that can be effectively isolated with magnetic‐activated cell sorting (MACS).

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Endogenous Mas‐related G‐protein‐coupled receptor X1 activates and sensitizes TRPA1 in a human model of peripheral nerves

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 9 publications

References 58 publications

Microinjection of pruritogens in NGF-sensitized human skin

Microinjection of pruritogens in NGF-sensitized human skin

Defects in early synaptic formation and neuronal function in Prader-Willi syndrome

Immunological isolation and characterization of neuronal progenitors from human dental pulp: A laboratory‐based investigation

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