The long-term objective of this proposal is to understand how cell surface receptors and ion channels detect extracellular signals and transduce this information into physiological changes at the cellular and organismal level. This project will focus on two members of the TRP channel family that are expressed on primary afferent neurons of the pain pathway and mediate thermosensation in the mammalian peripheral nervous system. TRPV1 is an excitatory ion channel that is activated by noxious heat or capsaicin, the pungent ingredient in chili peppers. Electrophysiological and genetic studies have shown that TRPV1 contributes to the detection of noxious heat in vivo and is modulated by a variety of inflammatory agents (e.g. extracellular protons, bioactive lipids, nerve growth factor, and bradykinin), making it an essential component of the signaling pathway through which injury increases sensitivity to heat. TRPM8 is a cold-activated channel that also responds to menthol and other cooling compounds. Determining how these channels detect thermal and chemical stimuli will provide important insight into the basic molecular processes that underlie nociception and pain sensation under normal and pathological conditions. This information will also stimulate the design and development of novel analgesic agents for treating peripheral pain syndromes, such as those associated with rheumatoid arthritis, viral and diabetic neuropathies, or peri-operative wound healing. A combination of molecular genetic, biochemical, and electrophysiological methods will be used to probe the mechanisms whereby TRPV1 and TRPM8 detect and respond to chemical and physical stimuli that produce or exacerbate pain.
The specific aims of the proposal are to: (i) delineate regions of TRPV1 that are required for modulation by phospholipase C and phospholipid interaction; (ii) pinpoint domains of TRPV1 that interact with TrkA, the receptor for nerve growth factor; (iii) delineate regions of TRPM8 that are required for detection of menthol and cold; (iv) determine whether and how TRPM8 is regulated by inflammatory agents or prolonged exposure to cold (i.e. adaptation).
|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|
|Gracheva, Elena O; Cordero-Morales, Julio F; González-Carcacía, José A et al. (2011) Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. Nature 476:88-91|
|Cavanaugh, Daniel J; Chesler, Alexander T; Jackson, Alexander C et al. (2011) Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci 31:5067-77|
|Cavanaugh, Daniel J; Chesler, Alexander T; Bráz, Joao M et al. (2011) Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons. J Neurosci 31:10119-27|
|Gracheva, Elena O; Ingolia, Nicholas T; Kelly, Yvonne M et al. (2010) Molecular basis of infrared detection by snakes. Nature 464:1006-11|
|Bohlen, Christopher J; Priel, Avi; Zhou, Sharleen et al. (2010) A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell 141:834-45|
|Basbaum, Allan I; Bautista, Diana M; Scherrer, Grégory et al. (2009) Cellular and molecular mechanisms of pain. Cell 139:267-84|
|Myers, Benjamin R; Bohlen, Christopher J; Julius, David (2008) A yeast genetic screen reveals a critical role for the pore helix domain in TRP channel gating. Neuron 58:362-73|