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.
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.
| Jabba, Sairam; Goyal, Raman; Sosa-Pagán, Jason O et al. (2014) Directionality of temperature activation in mouse TRPA1 ion channel can be inverted by single-point mutations in ankyrin repeat six. Neuron 82:1017-31 |
| Kim, Sung Eun; Patapoutian, Ardem; Grandl, Jörg (2013) Single residues in the outer pore of TRPV1 and TRPV3 have temperature-dependent conformations. PLoS One 8:e59593 |
| Coste, Bertrand; Xiao, Bailong; Santos, Jose S et al. (2012) Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 483:176-81 |
| 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 |
| 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 |
| 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 |
| Dhaka, Ajay; Uzzell, Valerie; Dubin, Adrienne E et al. (2009) TRPV1 is activated by both acidic and basic pH. J Neurosci 29:153-8 |
| Hu, Hongzhen; Bandell, Michael; Petrus, Matt J et al. (2009) Zinc activates damage-sensing TRPA1 ion channels. Nat Chem Biol 5:183-90 |
Showing the most recent 10 out of 23 publications
