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The Journal of Neuroscience, December 17, 2008, 28(51):13727-13737; doi:10.1523/JNEUROSCI.5741-07.2008
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Cellular/Molecular
Overexpressed Transient Receptor Potential Vanilloid 3 Ion Channels in Skin Keratinocytes Modulate Pain Sensitivity via Prostaglandin E2
Susan M. Huang,1,2,3 * Hyosang Lee,1,2,3 * Man-Kyo Chung,1,2,3 Una Park,1,2,3 Yin Yin Yu,1,2,3 Heather B. Bradshaw,5,6 Pierre A. Coulombe,1,4 J. Michael Walker,5,6 andMichael J. Caterina1,2,3 1Department of Biological Chemistry, 2Solomon H. Snyder Department of Neuroscience, 3Center for Sensory Biology, and 4Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21025, and 5Gill Center for Biomolecular Science and 6Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405
Correspondence should be addressed to Michael J. Caterina, Department of Biological Chemistry, Solomon H. Snyder Department of Neuroscience and Center for Sensory Biology, Room 408 Biophysics Building, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205. Email: caterina{at}jhmi.edu
The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E2 (PGE2) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-7203212, however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE2.
Key words: temperature; TRPV; heat; transgenic; channel; nociception
Received Dec. 28, 2007; revised Oct. 23, 2008; accepted Oct. 27, 2008.
Correspondence should be addressed to Michael J. Caterina, Department of Biological Chemistry, Solomon H. Snyder Department of Neuroscience and Center for Sensory Biology, Room 408 Biophysics Building, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205. Email: caterina{at}jhmi.edu
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