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

Manouela V. Valtcheva, Steve Davidson, Chengshui Zhao, Michael Leitges, Robert W. Gereau

Research output: Contribution to journalArticle

Abstract

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 q PCR), 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.

Original languageEnglish (US)
Article number1
JournalMolecular Pain
Volume11
Issue number1
DOIs
StatePublished - Jan 6 2015
Externally publishedYes

Fingerprint

Protein Kinase C
Histamine
Neurons
Chloroquine
Protein Isoforms
Alanine
Spinal Ganglia
Knockout Mice
Capsaicin
Sensory Receptor Cells
G-Protein-Coupled Receptors
Pharmacology
Calcium
Skin
Peptides

Keywords

  • Novel PKC
  • Peptide inhibitor
  • PKC isoform
  • PKCdelta
  • Pruritus

ASJC Scopus subject areas

  • Molecular Medicine
  • Cellular and Molecular Neuroscience
  • Anesthesiology and Pain Medicine

Cite this

Protein kinase Cδ mediates histamine-evoked itch and responses in pruriceptors. / Valtcheva, Manouela V.; Davidson, Steve; Zhao, Chengshui; Leitges, Michael; Gereau, Robert W.

In: Molecular Pain, Vol. 11, No. 1, 1, 06.01.2015.

Research output: Contribution to journalArticle

Valtcheva, Manouela V. ; Davidson, Steve ; Zhao, Chengshui ; Leitges, Michael ; Gereau, Robert W. / Protein kinase Cδ mediates histamine-evoked itch and responses in pruriceptors. In: Molecular Pain. 2015 ; Vol. 11, No. 1.
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abstract = "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 q PCR), 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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