Thermal sensation and pain use ion channels for detection of environmental cues. Thermal TRP channels, members of the transient receptor potential superfamily, are the principal detectors of thermal stimuli. These channels have a steep temperature dependence compared to other proteins. The long term goal of this research is to understand how the channels obtain their strong thermal sensitivity. We will focus on the vanilloid receptor TRPV1, a founding member of the thermal TRP subfamily. The channel plays a pivotal role in pain transduction and is abundantly expressed in peripheral sensory neurons where it appears to act as a gateway for detection and integration of noxious stimuli. Our previous research made progress in identifying the origin of thermal sensitivity of TRPV1, and showed that the channel contains modular thermal sensor domains in its N-terminus. We propose to take advantage of these findings to perform a comprehensive biophysical study on the fundamental mechanisms of temperature-dependent gating, using approaches that have proven successful for understanding other types of ion channel gating.
Aim 1 focuses on the physical basis of thermal sensors. The hypothesis to be tested is that the N-terminal domain is responsible for distinct temperature phenotypes of TRPV1 homologs. By dissecting the molecular determinants of the phenotypic differences, we will identify the residues and subdomains contributing to temperature sensing.
Aim 2 examines the interactions between sensing domains and subunits. We will test the cooperativity of thermal sensing between subunits, delineate the contribution of individual subunit thermal sensing events to channel opening, and probe the influence of thermal sensitivity by other stimuli. The results will unravel complex mechanisms by which TRPV1 achieves a dynamic thermal sensitivity for its physiological function over broad temperature ranges.
Aim 3 addresses the coupling of the thermal sensor domain with the channel gate. We will test several regions throughout the channel and determine the allosteric mechanisms by which they control temperature activation. The results will illuminate the temperature-gating pathway in TRPV1 that links thermal sensing and gating. Our approach involves patch-clamp recording from recombinant channels in heterologous expression systems, combined with fast temperature stimulation and kinetic analysis to unravel the molecular events occurring during activation, along with mutagenesis to identify functional domains of the receptor. Thermal TRP channels are attractive ion-channel targets for the development of novel analgesic drugs that could act peripherally at nociceptors where pain is generated. With insight into how the channels function, the proposed studies will help prompt the selective drug development for treatment of pathologies such as thermal hyperalgesia due to inflammation, peripheral nerve injury, diabetes and herpes simplex.

Public Health Relevance

Pain is among the most common symptoms for which patients seek medical attention. Vanilloid receptors play a pivotal role in pain transduction, and are abundantly expressed in peripheral nerve endings. The proposed studies will provide new knowledge on how the channels function, which is important for understanding actions of drugs interacting with the channels and for selective development of novel modes of analgesics that act peripherally with fewer side-effects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-N (04))
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Dunsmore, Sarah
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State University of New York at Buffalo
Schools of Medicine
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Liu, Beiying; Qin, Feng (2017) Single-residue molecular switch for high-temperature dependence of vanilloid receptor TRPV3. Proc Natl Acad Sci U S A 114:1589-1594
Liu, Beiying; Qin, Feng (2016) Use Dependence of Heat Sensitivity of Vanilloid Receptor TRPV2. Biophys J 110:1523-1537
Wen, Han; Qin, Feng; Zheng, Wenjun (2016) Toward elucidating the heat activation mechanism of the TRPV1 channel gating by molecular dynamics simulation. Proteins 84:1938-1949
Liu, Beiying; Qin, Feng (2015) The Xenopus tropicalis orthologue of TRPV3 is heat sensitive. J Gen Physiol 146:411-21
Zheng, Wenjun; Qin, Feng (2015) A combined coarse-grained and all-atom simulation of TRPV1 channel gating and heat activation. J Gen Physiol 145:443-56
Qin, Feng (2013) Demystifying thermal channels: driving a channel both forwards and backwards with a single gear? Biophys J 104:2118-20
Cao, Erhu; Cordero-Morales, Julio F; Liu, Beiying et al. (2013) TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids. Neuron 77:667-79
Wu, Ying; Liu, Yongfeng; Hou, Panpan et al. (2013) TRPV1 channels are functionally coupled with BK(mSlo1) channels in rat dorsal root ganglion (DRG) neurons. PLoS One 8:e78203
Yao, Jing; Liu, Beiying; Qin, Feng (2011) Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels. Proc Natl Acad Sci U S A 108:11109-14
Liu, Beiying; Yao, Jing; Zhu, Michael X et al. (2011) Hysteresis of gating underlines sensitization of TRPV3 channels. J Gen Physiol 138:509-20