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

Molecular Pain

Robert W Gereau²  Michael Leitges¹  Chengshui Zhao²  Steve Davidson²  Manouela V Valtcheva³ 

[1] Biotechnology Centre of Oslo, University of Oslo, Blindern N-0317, Oslo, Norway;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

关键词: Pruritus;    Peptide inhibitor;    Novel PKC;    PKCdelta;    PKC isoform;   

Others  :  1135549
DOI  :  10.1186/1744-8069-11-1

 received in 2014-09-23, accepted in 2014-12-23,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Valtcheva et al.; licensee BioMed Central.

【 图 表 】

Figure 4.

Figure 2.

Figure 3.

Figure 4.

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