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      Protein kinase Cδ mediates histamine-evoked itch and responses in pruriceptors

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          Abstract

          Background

          Itch-producing compounds stimulate receptors expressed on small diameter fibers that innervate the skin. Many of the currently known pruritogen receptors are G q Protein-Coupled Receptors (G qPCR), which activate Protein Kinase C (PKC). Specific isoforms of PKC have been previously shown to perform selective functions; however, the roles of PKC isoforms in regulating itch remain unclear. In this study, we investigated the novel PKC isoform PKCδ as an intracellular modulator of itch signaling in response to histamine and the non-histaminergic pruritogens chloroquine and β-alanine.

          Results

          Behavioral experiments indicate that PKCδ knock-out (KO) mice have a 40% reduction in histamine-induced scratching when compared to their wild type littermates. On the other hand, there were no differences between the two groups in scratching induced by the MRGPR agonists chloroquine or β-alanine. PKCδ was present in small diameter dorsal root ganglion (DRG) neurons. Of PKCδ-expressing neurons, 55% also stained for the non-peptidergic marker IB4, while a smaller percentage (15%) expressed the peptidergic marker CGRP. Twenty-nine percent of PKCδ-expressing neurons also expressed TRPV1. Calcium imaging studies of acutely dissociated DRG neurons from PKCδ-KO mice show a 40% reduction in the total number of neurons responsive to histamine. In contrast, there was no difference in the number of capsaicin-responsive neurons between KO and WT animals. Acute pharmacological inhibition of PKCδ with an isoform-specific peptide inhibitor (δV1-1) also significantly reduced the number of histamine-responsive sensory neurons.

          Conclusions

          Our findings indicate that PKCδ plays a role in mediating histamine-induced itch, but may be dispensable for chloroquine- and β-alanine-induced itch.

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          Most cited references 66

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          Genetic dissection of an amygdala microcircuit that gates conditioned fear

          The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. We used molecular genetic approaches to map the functional connectivity of a subpopulation of GABAergic neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-delta (PKCδ). Channelrhodopsin-2 assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKCδ+ neurons inhibit output neurons in the medial CE (CEm), and also make reciprocal inhibitory synapses with PKCδ− neurons in CEl. Electrical silencing of PKCδ+ neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus (CS), called CEloff units (Ciocchi et al, this issue). This correspondence, together with behavioral data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.
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            The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.

            Atopic dermatitis (AD) is a chronic itch and inflammatory disorder of the skin that affects one in ten people. 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. Copyright © 2013 Elsevier Inc. All rights reserved.
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              TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch

              SUMMARY Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. In many cases, pathological itch is insensitive to antihistamine treatment. Recent studies have identified members of the Mas-related GPCR (Mrgpr) family that are activated by mast cell mediators and promote histamine-independent itch. MrgprA3 and MrgprC11 act as receptors for the pruritogens chloroquine and BAM8–22, respectively. However, the signaling pathways and transduction channels activated downstream of these pruritogens are largely unknown. We found that TRPA1 is the downstream target of both MrgprA3 and MrgprC11, in cultured sensory neurons and heterologous cells. TRPA1 is required for Mrgpr-mediated signaling, as sensory neurons from TRPA1-deficient mice exhibited profoundly diminished responses to chloroquine and BAM8–22. Likewise, TRPA1-deficient mice displayed little to no scratching in response to these pruritogens. Our findings demonstrate that TRPA1 is an essential component of the signaling pathways that promote histamine-independent itch.
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                Author and article information

                Contributors
                valtchevam@wusm.wustl.edu
                sdavidson@wustl.edu
                zhaoc@anest.wustl.edu
                michael.leitges@biotek.uio.no
                gereaur@wustl.edu
                Journal
                Mol Pain
                Mol Pain
                Molecular Pain
                BioMed Central (London )
                1744-8069
                6 January 2015
                6 January 2015
                2015
                : 11
                : 1
                Affiliations
                [ ]Washington University Pain Center and Department of Anesthesiology, Washington University in St. Louis, 660 S. Euclid Ave, Box 8054, 63110 St. Louis, MO USA
                [ ]Medical Scientist Training Program, Washington University in St. Louis, St. Louis, MO 63110 USA
                [ ]Biotechnology Centre of Oslo, University of Oslo, Blindern, N-0317 Oslo, Norway
                Article
                712
                10.1186/1744-8069-11-1
                4298070
                25558916
                © Valtcheva et al.; licensee BioMed Central. 2015

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                Research
                Custom metadata
                © The Author(s) 2015

                Molecular medicine

                pkc isoform, pkcdelta, novel pkc, peptide inhibitor, pruritus

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