Acute and chronic pain represent significant and under-treated health problems in the U.S. due, in part, to our incomplete understanding of the mechanisms by which the peripheral nervous system detects noxious stimuli. TRPV1 is a heat-gated ion channel required for some, but not all aspects of heat-evoked pain. Three related channels, TRPV2, TRPV3, and TRPV4, can also be activated by elevated temperatures and therefore may contribute to the detection of painful heat. TRPV2 is activated at very high temperatures (>52 degrees C) and expressed most highly in a subset of sensory neurons. TRPV3 and TRPV4 are activated at temperatures >32 degrees C. In the skin, TRPV3 and TRPV4 expression is most prominent in epithelial keratinocytes, raising the possibility that these cells participate in an indirect mode of thermosensation involving TRPV3 and TRPV4. TRPV2 and TRPV4 can also be activated by cell swelling, suggesting that they may participate in mechanosensation. This proposal is aimed at achieving the following goals: (1) To determine whether and how TRPV2 and TRPV4 contribute to the detection of painful and nonpainful thermal and mechanical stimuli. (2) To determine whether keratinocyte TRPV3 and TRPV4 contribute to noxious and/or innocuous thermosensation and mechanosensation. (3) To determine how keratinocytes communicate the presence of thermal stimuli to adjacent sensory neurons. To achieve these goals, TRPV2 and TRPV4 null mutant mice will be analyzed for acute responsiveness to mechanical and thermal stimuli and for enhancement of thermo- or mechanosensitivity following inflammation or nerve injury. Wild-type or dominant negative forms of TRPV3 or TRPV4 will be overexpressed selectively in keratinocytes and the effects on thermosensation evaluated behaviorally. Finally, biochemical electrophysiological, fluorescent calcium imaging, and behavioral methods will be used to identify molecules through which heat-exposed keratinocytes communicate with nearby sensory neurons.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Huang, Susan M; Li, Xiaoxin; Yu, YinYin et al. (2011) TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. Mol Pain 7:37
Park, Una; Vastani, Nisha; Guan, Yun et al. (2011) TRP vanilloid 2 knock-out mice are susceptible to perinatal lethality but display normal thermal and mechanical nociception. J Neurosci 31:11425-36
Link, Tiffany M; Park, Una; Vonakis, Becky M et al. (2010) TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat Immunol 11:232-9
Moussaieff, Arieh; Rimmerman, Neta; Bregman, Tatiana et al. (2008) Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain. FASEB J 22:3024-34
Huang, Susan M; Lee, Hyosang; Chung, Man-Kyo et al. (2008) Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2. J Neurosci 28:13727-37
Chung, Man-Kyo; Guler, Ali D; Caterina, Michael J (2008) TRPV1 shows dynamic ionic selectivity during agonist stimulation. Nat Neurosci 11:555-64
Birder, Lori; Kullmann, F Aura; Lee, Hyosang et al. (2007) Activation of urothelial transient receptor potential vanilloid 4 by 4alpha-phorbol 12,13-didecanoate contributes to altered bladder reflexes in the rat. J Pharmacol Exp Ther 323:227-35
Caterina, Michael J (2007) Transient receptor potential ion channels as participants in thermosensation and thermoregulation. Am J Physiol Regul Integr Comp Physiol 292:R64-76
Sidhaye, Venkataramana K; Guler, Ali D; Schweitzer, Kelly S et al. (2006) Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions. Proc Natl Acad Sci U S A 103:4747-52