Journal club 2013-07-26

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 2013-07-26 Read More »

Journal club 2013-07-19

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 2013-07-19 Read More »

Journal club 2013-07-12

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 2013-07-12 Read More »

Journal club 2013-06-14

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.

Journal club 2013-06-14 Read More »

Journal club 2013-06-07

Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons

David P Roberson1,2, Sagi Gudes3,4,8, Jared M Sprague1,5,8, Haley A W Patoski1, Victoria K Robson1, Felix Blasl3, Bo Duan2,6, Seog Bae Oh1,7, Bruce P Bean2, Qiufu Ma2,6, Alexander M Binshtok3,4 & Clifford J Woolf1,2

nn.3404 nn.3404-S1

The peripheral terminals of primary sensory neurons detect histamine and non-histamine itch-provoking ligands through molecularly distinct transduction mechanisms. It remains unclear, however, whether these distinct pruritogens activate the same or different afferent fibers. Using a strategy of reversibly silencing specific subsets of murine pruritogen-sensitive sensory axons by targeted delivery of a charged sodium-channel blocker, we found that functional blockade of histamine itch did not affect the itch evoked by chloroquine or SLIGRL-NH2, and vice versa. Notably, blocking itch-generating fibers did not reduce pain-associated behavior. However, silencing TRPV1+ or TRPA1+ neurons allowed allyl isothiocyanate or capsaicin, respectively, to evoke itch, implying that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These findings support the presence of functionally distinct sets of itch-generating neurons and suggest that targeted silencing
of activated sensory fibers may represent a clinically useful anti-pruritic therapeutic approach for histaminergic and non- histaminergic pruritus.

Journal club 2013-06-07 Read More »

Journal club 2013-05-31

The Cells and Circuitry for Itch Responses in Mice

Santosh K. Mishra and Mark A. Hoon*

www.sciencemag.org_content_340_6135_968.full

www.sciencemag.org_content_suppl_2013_05_23_340.6135.968.DC1_Mishra-SM

Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb−/− mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb−/− mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor–expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next
two stages of this dedicated neuronal pathway.

Journal club 2013-05-31 Read More »

Journal club 2013-05-24

1-s2.0-S0306452212009220-main

Cross-sensitization of histamine-independent itch in mouse primary sensory neurons

  • University of California, Davis, Department of Neurobiology, Physiology & Behavior, 1 Shields Avenue, Davis, CA 95616, United States

Accepted 8 September 2012
Available online 19 September 2012

 

Abstract

Overexpression of pruritogens and their precursors may contribute to the sensitization of histamine-dependent and –independent itch-signaling pathways in chronic itch. We presently investigated self- and cross-sensitization of scratching behavior elicited by various pruritogens, and their effects on primary sensory neurons. The MrgprC11 agonist BAM8-22 exhibited self- and reciprocal cross-sensitization of scratching evoked by the protease-activated receptor-2 (PAR-2) agonist SLIGRL. The MrgprA3 agonist chloroquine unidirectionally cross-sensitized BAM8-22-evoked scratching. Histamine unidirectionally cross-sensitized scratching evoked by chloroquine and BAM8-22. SLIGRL unidirectionally cross-sensitized scratching evoked by chloroquine. Dorsal root ganglion (DRG) cells responded to various combinations of pruritogens and algogens. Neither chloroquine, BAM8-22 nor histamine had any effect on responses of DRG cell responses to subsequently applied pruritogens, implying that their behavioral self- and cross-sensitization effects are mediated indirectly. SLIGRL unilaterally cross-sensitized responses of DRG cells to chloroquine and BAM8-22, consistent with the behavioral data. These results indicate that unidirectional cross-sensitization of histamine-independent itch-signaling pathways might occur at a peripheral site through PAR-2. PAR-2 expressed in pruriceptive nerve endings is a potential target to reduce sensitization associated with chronic itch.

Journal club 2013-05-24 Read More »

Journal club 2013-05-10

The TGR5 receptor mediates bile acid– induced itch and analgesia

64551

Farzad Alemi,1 Edwin Kwon,1 Daniel P. Poole,2 TinaMarie Lieu,3 Victoria Lyo,1 Fiore Cattaruzza,1 Ferda Cevikbas,4 Martin Steinhoff,4 Romina Nassini,5 Serena Materazzi,5 Raquel Guerrero-Alba,6 Eduardo Valdez-Morales,6 Graeme S. Cottrell,7 Kristina Schoonjans,8 Pierangelo Geppetti,5 Stephen J. Vanner,6 Nigel W. Bunnett,3 and Carlos U. Corvera1

1Department of Surgery, UCSF, San Francisco, California, USA. 2Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia. 3Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia. 4Department of Dermatology, UCSF, San Francisco, California, USA. 5Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. 6Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen’s University, Kingston, Ontario, Canada. 7Department of Pharmacy and Pharmacology, The University of Bath, Bath, United Kingdom. 8Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, School of Life Sciences, Lausanne, Switzerland.

Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symp- toms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cho- lestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neu- rons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine- enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide– and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

Journal club 2013-05-10 Read More »

Journal club 2013-04-30

2383.full
Filename : 2383-full.pdf (969 KB)
Caption :

Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2383-8. doi: 10.1073/pnas.1215555110. Epub 2013 Jan 23.

UV light phototransduction activates transient receptor potential A1 ion channels in human melanocytes.

Source

Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.

Abstract

Human skin is constantly exposed to solar ultraviolet radiation (UVR), the most prevalent environmental carcinogen. Humans have the unique ability among mammals to respond to UVR by increasing their skin pigmentation, a protective process driven by melanin synthesis in epidermalmelanocytes. The molecular mechanisms used by melanocytes to detect and respond to long-wavelength UVR (UVA) are not well understood. We recently identified a UVA phototransduction pathway in melanocytes that is mediated by G protein-coupled receptors and leads to rapid calcium mobilization. Here we report that in human epidermal melanocytes physiological doses of UVR activate a retinal-dependent current mediated bytransient receptor potential A1 (TRPA1) ion channels. The TRPA1 photocurrent is UVA-specific and requires G protein and phospholipase C signaling, thus contributing to UVA-induced calcium responses to mediate downstream cellular effects and providing evidence for TRPA1 function in mammalianphototransduction. Remarkably, TRPA1 activation is required for the UVR-induced and retinal-dependent early increase in cellular melanin. Our results show that TRPA1 is essential for a unique extraocular phototransduction pathway in human melanocytes that is activated by physiological doses of UVR and results in early melanin synthesis.

Journal club 2013-04-30 Read More »

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