The sense of touch is unique in perceiving stimuli both physical (temperature, mechanical) and chemical (compounds that cause pain, itch, et cetera) in nature. In each modality, touch neurons distinguish noxious (painful) from innocuous stimuli, and the sensitization of touch neurons in response to injury and inflammation is the basis for many clinically-relevant chronic pain states. The molecules that mediate detection of touch stimuli have been a long-standing mystery. Recently, we and others have identified and characterized molecules responsible for sensing environmental temperature. These proteins are ion channels activated by distinct changes in thermal energy (in the noxious to innocuous range), thus functioning as the molecular thermometers of our body. We have found these same ion channels also act as chemosensors, and at least one of them is a polymodal sensor of physical and chemical damage. We wish to understand the activation process of thermoTRPs. Most fundamentally, how do these channels actually sense temperature at the molecular level? We will use a high- throughput random mutagenesis approach to address mechanism of thermoTRP activation. Our long-term goal is to synthesize a detailed molecular understanding of somatosensory neuron function. These studies aim to expand the fundamental understanding of basic sensory biology and are also expected to contribute to novel insights to treating pain.

Public Health Relevance

The studies described in this grant will address how ion channels involved in sensing pain and temperature are regulated. Information from these studies could potentially help in designing analgesic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046303-09
Application #
8231287
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Gnadt, James W
Project Start
2003-07-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$407,098
Indirect Cost
$192,723
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kim, Sung Eun; Patapoutian, Ardem; Grandl, Jorg (2013) Single residues in the outer pore of TRPV1 and TRPV3 have temperature-dependent conformations. PLoS One 8:e59593
Miyamoto, Takashi; Petrus, Matt J; Dubin, Adrienne E et al. (2011) TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin. Nat Commun 2:369
Xiao, Bailong; Coste, Bertrand; Mathur, Jayanti et al. (2011) Temperature-dependent STIM1 activation induces Ca²+ influx and modulates gene expression. Nat Chem Biol 7:351-8
Dubin, Adrienne E; Patapoutian, Ardem (2010) Nociceptors: the sensors of the pain pathway. J Clin Invest 120:3760-72
Grandl, Jorg; Kim, Sung Eun; Uzzell, Valerie et al. (2010) Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain. Nat Neurosci 13:708-14
Coste, Bertrand; Mathur, Jayanti; Schmidt, Manuela et al. (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330:55-60
Hu, Hongzhen; Bandell, Michael; Petrus, Matt J et al. (2009) Zinc activates damage-sensing TRPA1 ion channels. Nat Chem Biol 5:183-90
Dhaka, Ajay; Uzzell, Valerie; Dubin, Adrienne E et al. (2009) TRPV1 is activated by both acidic and basic pH. J Neurosci 29:153-8
Schmidt, Manuela; Dubin, Adrienne E; Petrus, Matt J et al. (2009) Nociceptive signals induce trafficking of TRPA1 to the plasma membrane. Neuron 64:498-509
Xiao, Bailong; Dubin, Adrienne E; Bursulaya, Badry et al. (2008) Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels. J Neurosci 28:9640-51

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