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David Julius Ph.D.

Molecular biology of sensory transduction and neurotransmitter action in the mammalian nervous system

David Julius Ph.D.

We are interested in the molecular biology of sensory transduction and neurotransmitter action in the mammalian nervous system. One of our goals is to understand the molecular basis of somatosensation - the process whereby we experience touch and temperature - with an emphasis on identifying molecules that detect noxious (pain-producing) stimuli. We are also interested in understanding how somatosensation is altered in response to tissue or nerve injury.

Our approach has been to identify molecular targets for drugs or natural products that mimic the psychophysical effects of commonly encountered somatosensory stimuli, such as heat or cold. Thus, we have asked how capsaicin, the main pungent ingredient in "hot" chili peppers, elicits a sensation of burning pain. Using a combination of molecular genetic, electrophysiological, and histological methods, we have shown that capsaicin activates an excitatory ion channel (called TRPV1) on sensory nerve endings. Remarkably, TRPV1 is also activated by heat (>43¼C), and we have used transgenic methods to demonstrate that this channel contributes to the detection of noxious heat in vivo and is essential for the development of thermal hypersensitivity following tissue injury. These findings have led us to ask how TRPV1 functions as a molecular integrator of physical and chemical signals that regulate sensory neuron excitability under normal and pathophysiological conditions.

On a related front, we have extended our molecular analysis of somatosensation by determining how we detect cold. Following the paradigm set forth by our work on the capsaicin receptor, we asked how cooling compounds, such as menthol, elicit a cool sensation. We have cloned a menthol receptor from primary sensory neurons and shown that it is also activated by cold thermal stimuli, proving that menthol elicits its familiar psychophysical sensation by activating a cold receptor. The structure of this menthol/cold receptor (TRPM8) resembles that of TRPV1, demonstrating that ion channels of this class serve as the principal sensors of thermal stimuli in the mammalian peripheral nervous system. Indeed, we have recently shown that mice deficient in TRPM8 display striking defects in cold and menthol sensitivity at the cellular and behavioral levels.

In more recent studies, we have identified another TRP channel (ANKTM1 or TRPA1) on sensory nerve fibers that is activated by allyl isothiocyanate, the pungent ingredient in wasabi and other mustards. Genetic and physiological evidence from our lab suggests that TRPA1 is an important component of the signaling mechanism through which certain pro-algesic agents depolarize sensory neurons to produce pain hypersensitivity and neurogenic inflammation.

In addition to our work on somatosensation and pain, we also study specific neurotransmitter receptor systems, such as those activated by serotonin or extracellular nucleotides. A recent example of our work in this area includes identification of the P2Y12 receptor, an ADP-activated G protein-coupled receptor that contributes to platelet aggregation and serves as the molecular target for the widely prescribed antithrombotic drugs, clopidogrel and ticlopidine. P2Y12R is also expressed by microglial cells in the brain and we have recently shown that this receptor modulates microglial activity to regulate injury responses in the central nervous system.
 

Selected publications:

Zeitz, K.P., Guy, N., Malmberg, A.B., Dirajlal, S., Martin, W.J., Sun, L., Bonhaus, D.W., Stucky, C.L., Julius, D. and Basbaum, A.I. (2002) The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J. Neurosci. 22: 1010-1019.

Jordt, S-E. and Julius, D. (2002) Molecular basis of species-specific sensitivity to ÒhotÓ chili peppers. Cell 108: 421-430.

McKemy, D.D., Neuhausser, W.M., and Julius, D. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature (Article) - advanced on-line publication, Feb. 10.

Prescott E and Julius D (2003) A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300: 1284-1288

Jordt S, McKemy D and Julius D (2003) Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr Opin Neurobiol 13: 487-492

Sanderson Nydahl K, Skinner K, Julius D and Basbaum A (2004) Co-localization of endomorphin-2 and substance P in primary afferent nociceptors and effects of injury: a light and electron microscopic study in the rat. Eur J Neurosci 19: 1789-1799

Lewinter R, Skinner K, Julius D and Basbaum A (2004) Immunoreactive TRPV-2 (VRL-1), a capsaicin receptor homolog, in the spinal cord of the rat. J Comp Neurol 470: 400-408

Jordt S, Bautista D, Chuang H, McKemy D, Zygmunt P, Högestätt E, Meng I and Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427: 260-265

Chuang H, Neuhausser W and Julius D (2004) The Super-Cooling Agent, Icilin, Reveals a Mechanism of Coincidence Detection by a Temperature-Sensitive TRP Channel. Neuron 43: 859-869

Julius D and Katz L (2004) A Nobel for Smell (Essay) Cell 119: 747-752

Ghilardi J, Röhrich H, Lindsay T, Sevcik M, Schwei M, Kubota K, Halvorson K, Poblete J, Chaplan S, Dubin A, Carruthers N, Swanson D, Kuskowski M, Flores C, Julius D and Mantyh P (2005) Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci 25: 3126-3131

Julius D. and Basbaum A.I. (2005) A neuropeptide courier for delta-opioid receptors? (Preview) Cell 122: 496-498

Bautista D, Movahed P, Hinman A, Axelsson H, Sterner O, Hogestatt E, Julius D, Jordt S and Zygmunt P (2005) Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci 102: 12248-12252

Bautista D, Jordt S, Nikai T, Tsuruda P, Read A, Poblete J, Yamoah E, Basbaum A and Julius D (2006) TRPA1 mediates the inflammatory action of environmental irritants and proalgesic agents. Cell 124: 1269– 1282

Basbaum A and Julius D (2006) Toward better pain control. Scientific American 294: 60-67

Marasco P, Tsuruda P, Bautista D, Julius D and Catania K (2006) Neuroanatomical evidence for segregation of nerve fibers conveying light touch and pain sensation in Eimer's organ of the mole. Proc Natl Acad Sci 103: 9339-9344

Tsuruda P, Julius D and Minor D (2006) Coiled-coils direct assembly of a cold-activated TRP channel. Neuron 51: 201-12

Siemens J, Zhou S, Piskorowski R, Nikai T, Lumpkin E, Basbaum A, King D, and Julius D (2006) Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444: 208-212

Haynes S, Hollopeter G, Yang G, Kurpius D, Dailey M, Gan W and Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nature Neurosci. 9: 1512-1519

Hinman A, Chuang H, Bautista D and Julius D (2006) TRP channel activation by reversible covalent modification. Proc Natl Acad Sci 103: 19564-19568

Bautista D, Siemens J, Glazer J, Tsuruda P, Basbaum A, Stucky C, Jordt S and Julius D (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448: 204-209

Myers B and Julius D (2007) TRP channel structural biology: new roles for an old fold (Preview). Neuron 54: 847-50

Trevisani M, Siemens J, Materazzi S, Bautista D, Nassini R, Campi B, Imamachi N, Andre E, Patacchini R, Cottrell G, Gatti R, Basbaum A, Bunnett N, Julius D, and Geppetti P (2007) 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci 104: 13519-24

McNamara C, Mandel-Brehm J, Bautista D, Siemens J, Deranian K, Zhao M, Hayward N, Chong J, Julius D, Moran M and Fanger C (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci 104: 13525-30

Myers BR, Bohlen CJ and Julius D (2008) A yeast genetic screen reveals critical gating residues in TRP channel pore helix domains. Neuron 58: 362-373

Bautista DM, Sigal, YM, Milstein AD, Garrison JL, Zorn JA, Tsuruda, PR, Nicoll RA and Julius D (2008) Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nature Neurosci 1: 772-779

Bhattacharya MR, Bautista DM, Wu K, Haeberle H, Lumpkin EA, Julius D (2008) Radial stretch reveals distinct populations of mechanosensitive mammalian somatosensory neurons. Proc Natl Acad Sci 105: 20015-20020

Myers BR, Saimi Y, Julius D, and Kung C (2008) Multiple unbiased prospective screens identify TRP channels and their conserved gating elements. J Gen Physiol 132: 481-6

Myers BR, Sigal YM, and Julius D (2009) Evolution of thermal response properties in a cold-activated TRP channel. PLoS ONE 4: e5741

Basbaum AI, Bautista DM, Scherrer, G and Julius D (2009) Cellular and molecular basis of pain – Leading Edge Review. Cell 139: 267-284

Elena O. Gracheva, Nicolas T. Ingolia, Yvonne M. Kelly, Julio F. Cordero-Morales, Gunther Hollopeter, Alexander T. Chesler, Elda E. Sánchez, John C. Perez, Jonathan S. Weissman, and David Julius (2010) Molecular Basis of Infrared Detection by Snakes. Nature 464(7291): 1006–1011.