The heat sensor TRPV1 channel is a polymodal receptor that plays a key role in mediating neuronal pain caused by various noxious stimuli. One such stimulus is extracellular acidification caused by inflammation, tissue damage and ischemia. Low pH is thought to activate TRPV1 both directly by serving as a channel activator and indirectly by potentiating the channel's response to other stimuli. How TRPV1 activation is controlled by pH as well as its relation to activation by heat, ligands, and endogenous channel modulators remains largely unknown. Importantly, the highly unique susceptibility of TRPV1 activity to a variety of physical and chemical factors makes the channel an attractive target for clinical intervention of pain. The overarching goal of our research is to understand the cellular sensing function of TRPV1 by elucidating molecular mechanisms underlying its polymodal activation by heat, capsaicin and other stimuli. In the proposed study we aim to reveal the structural and mechanistic nature of extracellular H+ regulation of TRPV1. As H+-induced TRPV1 activity has heat-dependent and agonist-dependent components, this investigation will also shed light on how heat and agonist control TRPV1 activity. We approach our goal through a combination of optical, electrophysiological, and molecular methods. In particular, we will apply a patch fluorometry approach to directly observe structural changes in the channel protein or the binding of regulatory molecules, using fluorophores as molecular sensors. Simultaneous fluorescent and electrical recordings permit direct correlation of structural changes to their effects on channel activation. Using these methods, we will address questions on how changes in pH, temperature, and the concentration of agonists are sensed by TRPV1, what channel structures convey these stimuli, and how these stimuli converge to control TRPV1 activation. Answers to these questions should directly benefit the development of new clinical tools for treating TRPV1- mediated neuronal pain.

Public Health Relevance

TRPV1 serves as a key molecular element in mediating low pH-induced neuronal pain due to inflammation, tissue damage and ischemia. Our research aims at understanding how TRPV1 activation is controlled by extracellular acidification and its relationship with heat- and agonist-induced channel activation, which will shed light on designing potential clinical intervention of pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072377-03
Application #
8525468
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Silberberg, Shai D
Project Start
2011-09-30
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$314,947
Indirect Cost
$103,853
Name
University of California Davis
Department
Physiology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Ma, Linlin; Yang, Fan; Vu, Simon et al. (2016) Exploring functional roles of TRPV1 intracellular domains with unstructured peptide-insertion screening. Sci Rep 6:33827
Yang, Fan; Vu, Simon; Yarov-Yarovoy, Vladimir et al. (2016) Rational design and validation of a vanilloid-sensitive TRPV2 ion channel. Proc Natl Acad Sci U S A 113:E3657-66
Ma, Linlin; Lee, Bo Hyun; Clifton, Heather et al. (2015) Nicotinic acid is a common regulator of heat-sensing TRPV1-4 ion channels. Sci Rep 5:8906
Yang, Shilong; Yang, Fan; Wei, Ningning et al. (2015) A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1. Nat Commun 6:8297
Lee, Bo Hyun; Zheng, Jie (2015) Proton block of proton-activated TRPV1 current. J Gen Physiol 146:147-59
Yang, Fan; Xiao, Xian; Cheng, Wei et al. (2015) Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat Chem Biol 11:518-24
Zheng, Jie; Ma, Linlin (2014) Structure and function of the thermoTRP channel pore. Curr Top Membr 74:233-57
Cao, Xu; Ma, Linlin; Yang, Fan et al. (2014) Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold. J Gen Physiol 143:75-90
Yang, Fan; Zheng, Jie (2014) High temperature sensitivity is intrinsic to voltage-gated potassium channels. Elife 3:e03255
Ma, Linlin; Lee, Bo Hyun; Mao, Rongrong et al. (2014) Nicotinic acid activates the capsaicin receptor TRPV1: Potential mechanism for cutaneous flushing. Arterioscler Thromb Vasc Biol 34:1272-80

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