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 understanding the biology of pain. This research concerns ion channels underlying nociception, in particular, the cloned vanilloid receptor TRPV1. Recent studies of the channel have shown a previously unsuspected level of complexity in its function and regulation and have implicated it in detection and integration of both exogenous noxious stimuli such as heat, vanilloids and acids and endogenous proinflammatory signals. The goal of the project is to determine, at the molecular level, how the receptor functions as a versatile noxious detector and integrator in response to various stimuli, using methods of single-channel electrophysiology combined with molecular biology.
The first aim will focus on the mechanisms of the polymodal activation of the channel. Experiments are proposed to determine whether the heat sensitivity is required by other stimuli to activate the channel and how the stimuli of different modality interact within the receptor. The work will also develop allosteric models that unify the polymodal gating of the channel. The second objective is to investigate the structural basis of the polymodal activation. The study will examine to what extent the gating machinery for different stimuli are separated and will delineate the molecular domains specific to each stimulus and determine their functional mechanisms.
The third aim concerns the desensitization and recovery of the channel. Experiments are proposed to quantify and establish the mechanisms of the depletion of phosphatidylinositol-45-bisphosphate (PIP2) caused by activation of TRPV1, and to elucidate the nature of the desensitized states. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065994-08
Application #
7860284
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Dunsmore, Sarah
Project Start
2002-08-01
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2010
Total Cost
$284,558
Indirect Cost
Name
State University of New York at Buffalo
Department
Physiology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
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
Yao, Jing; Liu, Beiying; Qin, Feng (2009) Rapid temperature jump by infrared diode laser irradiation for patch-clamp studies. Biophys J 96:3611-9
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; 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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