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

Mol Pain. 2015 Jan 6;11:1. doi: 10.1186/1744-8069-11-1.

Abstract

Background: Itch-producing compounds stimulate receptors expressed on small diameter fibers that innervate the skin. Many of the currently known pruritogen receptors are Gq Protein-Coupled Receptors (GqPCR), 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide
  • Calcium / metabolism
  • Capsaicin / pharmacology
  • Cells, Cultured
  • Chloroquine / adverse effects
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Down-Regulation / genetics*
  • Ganglia, Spinal / cytology
  • Histamine / adverse effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism*
  • Pruritus / chemically induced*
  • Pruritus / metabolism*
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • beta-Alanine / adverse effects

Substances

  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • beta-Alanine
  • Histamine
  • Chloroquine
  • Protein Kinase C-alpha
  • Calcitonin Gene-Related Peptide
  • Capsaicin
  • Calcium