Pain begins with transduction at peripheral nerve terminals of specialized sensory neurons called nociceptors. Understanding how these nociceptors respond to pain-producing stimuli is a key step towards the understanding of the biology of pain. This research concerns ion channels underlying nociception, in particular, the cloned VR 1 receptor, which detects and integrates multiple physical and chemical stimuli including heat, vanilloids and acids. Our goal is to understand, at the molecular level, how the receptor functions as a versatile noxious detector in response to various stimuli. Our approach involves patch-clamp recordings from recombinant channels in heterologous expression systems, combined with kinetic analysis to unravel the molecular events occurring during activation, along with mutagenesis to identify functional domains of the receptor. Our first objective is to understand how heat activates the channel. We will determine the energetic landscape of heat activation and explore the existence of possible heat sensors in the receptor and their structural basis. Our second objective is to investigate how capsaicin, the pungent ingredient in hot peppers, activates the channel. We will study the biophysical properties of the activation process regarding capsaicin binding, unbinding and channel gating, and determine their molecular basis. We will correlate heat and capsaicin activation pathways and examine whether different mechanisms are used for physical and chemical stimulus detection. The third objective is to understand how hyperalgesic mediators like acids sensitizes the channel. We will probe possible allosteric mechanisms by which proton binding promotes heat and capsaicin activation. The fourth objective is to investigate the voltage dependence of the channel. We will determine how the activation kinetics is altered by voltage and where the voltage sensitivity originates. The proposed research will improve our knowledge of nociceptive sensory transduction and will benefit clinical advances in pain therapy, in particular, the search for analgesic drugs that have an entirely new mode of action and an unprecedented selectivity for nociceptors.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Dunsmore, Sarah
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State University of New York at Buffalo
Schools of Medicine
United States
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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
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
Qin, Feng (2010) Hill coefficients of a polymodal Monod-Wyman-Changeux model for ion channel gating. Biophys J 99:L29-31
Yao, Jing; Liu, Beiying; Qin, Feng (2010) Kinetic and energetic analysis of thermally activated TRPV1 channels. Biophys J 99:1743-53
Yao, Jing; Liu, Beiying; Qin, Feng (2010) Pore turret of thermal TRP channels is not essential for temperature sensing. Proc Natl Acad Sci U S A 107:E125; author reply E126-7
Liu, Beiying; Yao, Jing; Wang, Yingwei et al. (2009) Proton inhibition of unitary currents of vanilloid receptors. J Gen Physiol 134:243-58
Yao, Jing; Liu, Beiying; Qin, Feng (2009) Rapid temperature jump by infrared diode laser irradiation for patch-clamp studies. Biophys J 96:3611-9
Yao, Jing; Qin, Feng (2009) Interaction with phosphoinositides confers adaptation onto the TRPV1 pain receptor. PLoS Biol 7:e46
Ryu, Sujung; Liu, Beiying; Yao, Jing et al. (2007) Uncoupling proton activation of vanilloid receptor TRPV1. J Neurosci 27:12797-807

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