Keratinocytes can modulate and directly initiate nociceptive responses

  1. Kyle M Baumbauer
  2. Jennifer J DeBerry
  3. Peter C Adelman
  4. Richard H Miller
  5. Junichi Hachisuka
  6. Kuan Hsien Lee
  7. Sarah E Ross
  8. H Richard Koerber
  9. Brian M Davis
  10. Kathryn M Albers  Is a corresponding author
  1. University of Connecticut, United States
  2. University of Alabama, United States
  3. University of Pittsburgh, United States

Abstract

How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can direct AP firing in nociceptor as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing.

Article and author information

Author details

  1. Kyle M Baumbauer

    School of Nursing, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jennifer J DeBerry

    Department of Anesthesiology, University of Alabama, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peter C Adelman

    Department of Neurobiology, Pittsburgh Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Richard H Miller

    Department of Neurobiology, Pittsburgh Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Junichi Hachisuka

    Department of Neurobiology, Pittsburgh Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kuan Hsien Lee

    Department of Neurobiology, Pittsburgh Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sarah E Ross

    Department of Neurobiology, Pittsburgh Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. H Richard Koerber

    Department of Neurobiology, Pittsburgh Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Brian M Davis

    Department of Neurobiology, Pittsburgh Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kathryn M Albers

    Department of Neurobiology, Pittsburgh Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    kaa2@pitt.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animals were handled in compliance with an approved Institutional Animal Care and Use Committee (IACUC) protocol (#14074296) of the University of Pittsburgh. All surgery was performed under appropriate anesthesia with every effort was made to minimize pain.

Copyright

© 2015, Baumbauer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kyle M Baumbauer
  2. Jennifer J DeBerry
  3. Peter C Adelman
  4. Richard H Miller
  5. Junichi Hachisuka
  6. Kuan Hsien Lee
  7. Sarah E Ross
  8. H Richard Koerber
  9. Brian M Davis
  10. Kathryn M Albers
(2015)
Keratinocytes can modulate and directly initiate nociceptive responses
eLife 4:e09674.
https://doi.org/10.7554/eLife.09674

Share this article

https://doi.org/10.7554/eLife.09674

Further reading

    1. Neuroscience
    Jian Dong, Mian Chen ... Matthijs Verhage
    Research Article

    Dense core vesicles (DCVs) transport and release various neuropeptides and neurotrophins that control diverse brain functions, but the DCV secretory pathway remains poorly understood. Here, we tested a prediction emerging from invertebrate studies about the crucial role of the intracellular trafficking GTPase Rab10, by assessing DCV exocytosis at single-cell resolution upon acute Rab10 depletion in mature mouse hippocampal neurons, to circumvent potential confounding effects of Rab10’s established role in neurite outgrowth. We observed a significant inhibition of DCV exocytosis in Rab10-depleted neurons, whereas synaptic vesicle exocytosis was unaffected. However, rather than a direct involvement in DCV trafficking, this effect was attributed to two ER-dependent processes, ER-regulated intracellular Ca2+ dynamics, and protein synthesis. Gene Ontology analysis of differentially expressed proteins upon Rab10 depletion identified substantial alterations in synaptic and ER/ribosomal proteins, including the Ca2+ pump SERCA2. In addition, ER morphology and dynamics were altered, ER Ca2+ levels were depleted, and Ca2+ homeostasis was impaired in Rab10-depleted neurons. However, Ca2+ entry using a Ca2+ ionophore still triggered less DCV exocytosis. Instead, leucine supplementation, which enhances protein synthesis, largely rescued DCV exocytosis deficiency. We conclude that Rab10 is required for neuropeptide release by maintaining Ca2+ dynamics and regulating protein synthesis. Furthermore, DCV exocytosis appeared more dependent on (acute) protein synthesis than synaptic vesicle exocytosis.

    1. Neuroscience
    Jakob Rupert, Dragomir Milovanovic
    Insight

    By influencing calcium homeostasis, local protein synthesis and the endoplasmic reticulum, a small protein called Rab10 emerges as a crucial cytoplasmic regulator of neuropeptide secretion.