Journal club 2013-11-01

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The Star-Nosed Mole Reveals Clues to the Molecular Basis of Mammalian Touch

Abstract

Little is known about the molecular mechanisms underlying mammalian touch transduction. To identify novel candidate transducers, we examined the molecular and cellular basis of touch in one of the most sensitive tactile organs in the animal kingdom, the star of the star-nosed mole. Our findings demonstrate that the trigeminal ganglia innervating the star are enriched in tactile-sensitive neurons, resulting in a higher proportion of light touch fibers and lower proportion of nociceptors compared to the dorsal root ganglia innervating the rest of the body. We exploit this difference using transcriptome analysis of the star-nosed mole sensory ganglia to identify novel candidate mammalian touch and pain transducers. The most enriched candidates are also expressed in mouse somatosesensory ganglia, suggesting they may mediate transduction in diverse species and are not unique to moles. These findings highlight the utility of examining diverse and specialized species to address fundamental questions in mammalian biology.

Citation: Gerhold KA, Pellegrino M, Tsunozaki M, Morita T, Leitch DB, et al. (2013) The Star-Nosed Mole Reveals Clues to the Molecular Basis of Mammalian Touch. PLoS ONE 8(1): e55001. doi:10.1371/journal.pone.0055001

Editor: Michael N. Nitabach, Yale School of Medicine, United States of America

Received: October 10, 2012; Accepted: December 21, 2012; Published: January 30, 2013

Copyright: © 2013 Gerhold et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors are supported by a U.S. National Institutes of Health Innovator Award DOD007123A, the Pew Scholars Program, and the McKnight Scholars Fund (to DMB) and NSF grant 0844743 (to KCC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
journal.pone.0055001

Journal Club 2013-10-11

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The Epithelial Cell-Derived Atopic Dermatitis Cytokine TSLP Activates Neurons to Induce Itch

Sarah R. Wilson,1,2,3 Lydia The ́ ,1,3 Lyn M. Batia,1 Katherine Beattie,1 George E. Katibah,1 Shannan P. McClain,1 Maurizio Pellegrino,1 Daniel M. Estandian,1 and Diana M. Bautista1,2,*
1Department of Molecular and Cell Biology
2Helen Wills Neuroscience Institute

University of California, Berkeley, Berkeley, CA 94720, USA 3These authors contributed equally to this work *Correspondence: dbautista@berkeley.edu

http://dx.doi.org/10.1016/j.cell.2013.08.057

1-s2.0-S009286741301088X-main

SUMMARY

Atopic dermatitis (AD) is a chronic itch and inflamma- tory disorder of the skin that affects one in ten peo- ple. Patients suffering from severe AD eventually progress to develop asthma and allergic rhinitis, in a process known as the ‘‘atopic march.’’ Signaling between epithelial cells and innate immune cells via the cytokine thymic stromal lymphopoietin (TSLP) is thought to drive AD and the atopic march. Here, we report that epithelial cells directly communicate to cutaneous sensory neurons via TSLP to promote itch. We identify the ORAI1/NFAT calcium signaling pathway as an essential regulator of TSLP release from keratinocytes, the primary epithelial cells of the skin. TSLP then acts directly on a subset of TRPA1-positive sensory neurons to trigger robust itch behaviors. Our results support a model whereby calcium-dependent TSLP release by keratinocytes activates both primary afferent neurons and immune cells to promote inflammatory responses in the skin and airways.

Journal club 2013-09-13

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9554.full

Transient Receptor Potential Canonical 3 (TRPC3) Is Required for IgG Immune Complex-Induced Excitation of the Rat Dorsal Root Ganglion Neurons

Chronic pain may accompany immune-related disorders with an elevated level of serum IgG immune complex (IgG-IC), but the underlying                        mechanisms are obscure. We previously demonstrated that IgG-IC directly excited a subpopulation of dorsal root ganglion (DRG)                        neurons through the neuronal Fc-gamma receptor I (FcγRI). This might be a mechanism linking IgG-IC to pain and hyperalgesia.                        The purpose of this study was to investigate the signaling pathways and transduction channels activated downstream of IgG-IC                        and FcγRI. In whole-cell recordings, IgG-IC induced a nonselective cation current (IIC) in the rat DRG neurons, carried by Ca2+ and Na+. The IIC was potentiated or attenuated by, respectively, lowering or increasing the intracellular Ca2+ buffering capacity, suggesting that this current was regulated by intracellular calcium. Single-cell RT-PCR revealed that                        transient receptor potential canonical 3 (TRPC3) mRNA was always coexpressed with FcγRI mRNA in the same DRG neuron. Moreover,                        ruthenium red (a general TRP channel blocker), BTP2 (a general TRPC channel inhibitor), and pyrazole-3 (a selective TRPC3                        blocker) each potently inhibited the IIC. Specific knockdown of TRPC3 using small interfering RNA attenuated the IgG-IC-induced Ca2+ response and the IIC. Additionally, the IIC was blocked by the tyrosine kinase Syk inhibitor OXSI-2, the phospholipase C (PLC) inhibitor neomycin, and either the inositol                        triphosphate (IP3) receptor antagonist 2-aminoethyldiphenylborinate or heparin. These results indicated that the activation of neuronal FcγRI                        triggers TRPC channels through the Syk–PLC–IP3 pathway and that TRPC3 is a key molecular target for the excitatory effect of IgG-IC on DRG neurons.

  • Received December 20, 2011.
  • Revision received May 20, 2012.
  • Accepted May 23, 2012.

Journal club 2013-09-06

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Essential Role for TRPC5 in Amygdala Function
and Fear-Related Behavior

1-s2.0-S0092867409003766-main PIIS0092867409003766.mmc1

Antonio Riccio,1,2 Yan Li,3 Jisook Moon,3,5 Kwang-Soo Kim,3 Kiersten S. Smith,3 Uwe Rudolph,3 Svetlana Gapon,1 Gui Lan Yao,2 Evgeny Tsvetkov,3 Scott J. Rodig,4 Ashlee Van’t Veer,3 Edward G. Meloni,3 William A. Carlezon Jr.,3 Vadim Y. Bolshakov,3,* and David E. Clapham1,2,*
1Department of Cardiology, Howard Hughes Medical Institute, Manton Center for Orphan Disease, Children’s Hospital Boston, Boston, MA 02115, USA

2Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
3Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
5Present address: College of Medicine, Pochon CHA University, 606-5 Yeoksam-dong, Gangnam-gu, Seoul 135-081, Republic of Korea *Correspondence: vadimb@mclean.harvard.edu (V.Y.B.), dclapham@enders.tch.harvard.edu (D.E.C.)
DOI 10.1016/j.cell.2009.03.039

SUMMARY

The transient receptor potential channel 5 (TRPC5) is predominantly expressed in the brain where it can form heterotetrameric complexes with TRPC1 and TRPC4 channel subunits. These excitatory, nonse- lective cationic channels are regulated by G protein, phospholipase C-coupled receptors. Here, we show that TRPC5

Journal club 2013-08-12

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1-s2.0-S0143416010001260-main

Cell Calcium. 2010 Oct;48(4):202-8. doi: 10.1016/j.ceca.2010.09.001. Epub 2010 Oct 12.

TRPM8 mediates cold and menthol allergies associated with mast cell activation.

Source

Sensory Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.

Abstract

Exposure to low temperatures often causes allergic responses or urticaria. Similarly, menthol, a common food additive is also known to cause urticaria, asthma, and rhinitis. However, despite the obvious clinical implications, the molecular mechanisms responsible for inducing allergic responses to low temperatures and menthol have not been determined. Because a non-selective cation channel, transient receptor potential subtype M8 (TRPM8) is activated by cold and menthol, we hypothesized that this channel mediates cold- and menthol-induced histamine release in mast cells. Here, we report that TRPM8 is expressed in the basophilic leukemia mast cell line, RBL-2H3, and that exposure to menthol or low temperatures induced Ca(2+) influx in RBL-2H3 cells, which was reversed by a TRPM8 blocker. Furthermore, menthol, a TRPM8 agonist, induced the dose-dependent release of histamine from RBL-2H3 cells. When TRPM8 transcripts were reduced by siRNA (small interfering RNA), menthol- and cold-induced Ca(2+) influx and histamine release were significantly reduced. In addition, subcutaneous injection of menthol evoked scratching, a typical histamine-induced response which was reversed by a TRPM8 blocker. Thus, our findings indicate that TRPM8 mediates the menthol- and cold-induced allergic responses of mast cells, and suggest that TRPM8 antagonists be viewed as potential treatments for cold- and menthol-induced allergies.

Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID:

 

20934218

 

[PubMed – indexed for MEDLINE]

Journal club 2013-07-26

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Human Mas-Related G Protein-Coupled Receptors-X1 Induce Chemokine Receptor 2 Expression in Rat Dorsal Root Ganglia Neurons and Release of Chemokine Ligand 2 from the Human LAD-2 Mast Cell Line

pone.0058756

Hans Ju ̈rgen Solinski1, Franziska Petermann2, Kathrin Rothe1, Ingrid Boekhoff1, Thomas Gudermann1, Andreas Breit1*

1Walther-Straub-Institut fu ̈r Pharmakologie und Toxikologie, Ludwig-Maximilians-Universita ̈t Mu ̈nchen, Munich, Germany, 2Department of Neurology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany

Abstract

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up- regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain.
Citation: Solinski HJ, Petermann F, Rothe K, Boekhoff I, Gudermann T, et al. (2013) Human Mas-Related G Protein-Coupled Receptors-X1 Induce Chemokine Receptor 2 Expression in Rat Dorsal Root Ganglia Neurons and Release of Chemokine Ligand 2 from the Human LAD-2 Mast Cell Line. PLoS ONE 8(3): e58756. doi:10.1371/journal.pone.0058756

Editor: Roland Seifert, Medical School of Hannover, United States of America Received January 18, 2013; Accepted February 6, 2013; Published March 7, 2013

Copyright: ß 2013 Solinski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by a grant from the ‘‘Deutsche Forschungsgemeinschaft’’ [grant BR 3346/3–1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.*

E-mail: andreas.breit@lrz.uni-muenchen.de

Journal club 2013-07-19

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Life Sci. 2006 Dec 14;80(2):89-97. Epub 2006 Aug 23.

Characterization of the transient receptor potential channels mediating lysophosphatidic acid-stimulated calcium mobilization in B lymphoblasts.

Source

Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, Toronto, ON, Canada M5T 1R8.

Abstract

Altered 1-oleoyl-lysophosphatidic acid (LPA, 100 microM)-stimulated calcium responses occur in B-lymphoblast cell lines from bipolar disorder patients, but the mechanism(s) involved is uncertain. Lysophosphatidic acid shares a structurally similar fatty acid side chain with the diacylglycerol analogue, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a known activator of subtypes 3, 6 and 7 of the canonical transient receptor potential (TRPC) cation channel subfamily. Accordingly, the objective of this study was to determine whether the LPA-stimulated calcium response in B-lymphoblasts is mediated, in part, through this TRPC channel subfamily. Divalent cation selectivity in response to thapsigargin, LPA and OAG were used to distinguish TRPC-like character of the responses to these agents in BLCLs. The sensitivity to gadolinium, an inhibitor of capacitative calcium channels, was used to determine the store-operated nature of the responses. The TRPC isoforms that are present in BLCLs as identified by immunoblotting and/or PCR include TRPC1, 3 and 5. Minimal barium influx in calcium-free buffer was observed following thapsigargin stimulation. However, LPA stimulated barium influx of a magnitude similar to that induced by OAG. Thapsigargin-provoked calcium influx was completely inhibited by gadolinium (10 microM), whereas LPA and OAG-stimulated responses were partially inhibited and potentiated, respectively. The results suggest that 100 microM LPA stimulates calcium entry through channels with characteristics similar to TRPC3, as TRPC6 and 7 are absent in B-lymphoblasts.

PMID:

 

16979191

 

[PubMed – indexed for MEDLINE]

Journal club 2013-07-12

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Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site

Andrés Nieto-Posadas1, Giovanni Picazo-Juárez1, Itzel Llorente1, Andrés Jara-Oseguera2,
Sara Morales-Lázaro1, Diana Escalante-Alcalde1*, León D Islas2* & Tamara Rosenbaum1*

Since 1992, there has been growing evidence that the bioactive phospholipid lysophosphatidic acid (LPA), whose amounts are
increased upon tissue injury, activates primary nociceptors resulting in neuropathic pain. The TRPV1 ion channel is expressed in
primary afferent nociceptors and is activated by physical and chemical stimuli. Here we show that in control mice LPA produces
acute pain-like behaviors, which are substantially reduced in Trpv1-null animals. Our data also demonstrate that LPA activates
TRPV1 through a unique mechanism that is independent of G protein–coupled receptors, contrary to what has been widely
shown for other ion channels, by directly interacting with the C terminus of the channel. We conclude that TRPV1 is a direct
molecular target of the pain-producing molecule LPA and that this constitutes, to our knowledge, the first example of LPA
binding directly to an ion channel to acutely regulate its function.

nchembio.712

Journal club 2013-06-14

By

jid2009155a

Leukotriene B(4) mediates sphingosylphosphorylcholine-induced itch-associated responses in mouse skin.

Source

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-1094, Japan.

Abstract

In atopic dermatitis, the concentration in the skin of sphingosylphosphorylcholine (SPC), which is produced from sphingomyelin by sphingomyelin deacylase, is increased. In the present study, we investigated the itch-eliciting activity of SPC and related substances and the mechanisms of SPC action in mice. An intradermal injection of SPC, but not sphingomyelin and sphingosine, induced scratching, an itch-associated response, which was not suppressed by a deficiency in mast cells or the H(1) histamine receptor antagonist terfenadine. The action of SPC was inhibited by the mu-opioid receptor antagonist naltrexone. SPC action also was inhibited by the 5-lipoxygenase inhibitor zileuton and the leukotriene B(4) antagonist ONO-4057, but not by the cyclooxygenase inhibitor indomethacin. Moreover, SPC action was inhibited by the antiallergic agent azelastine, which suppresses the action and production of leukotriene B(4). Administration of SPC to the skin and to primary cultures of keratinocytes increased leukotriene B(4) production. SPC increased intracellular Ca(2+) ion concentration in primary cultures of dorsal root ganglion neurons and keratinocytes. These results suggest that SPC induces itching through a direct action on primary afferents and leukotriene B(4) production of keratinocytes. Sphingomyelin deacylase and SPC receptors may be previously unreported targets for antipruritic drugs.

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