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Julius, David
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| Research Statement | | 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 VR1 or TRPV1) on sensory nerve endings. Remarkably, TRPV1 is also activated by heat (>43ºC), and we have used transgenic methods to demonstrate that this channel contributes to the detection of noxious heat in vivo. These studies have also shown that TRPV1 is essential for the development of thermal hypersensitivity following tissue injury, leading 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. Using an expression cloning approach, we have identified 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 (CMR1 or TRPM8) resembles that of TRPV1, demonstrating that ion channels of this class serve as the principle sensors of thermal stimuli in the mammalian peripheral nervous system.
Most recently, we have identified the molecular site of action of isothiocyanate compounds, which constitute the pungent ingredients in wasabi, yellow mustard and other plants of the Brassica family. Isothiocyanates produce pain and irritation by activating yet another member of the TRP channel family (ANKTM1 or TRPA1) that is expressed on sensory neurons. Our studies suggest that a normal physiological function of TRPA1 is to serve as a so-called receptor-operated channel, depolarizing sensory neurons in response to the activation of phospholipase C-coupled receptors by pro-algesic agents such as bradykinin, ATP, or histamine.
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 glial cells in the brain and we are asking whether this receptor contributes to neural development or response to injury. |
Publications | | Jordt, SE, Bautista, DM, Chuang, H, McKemy, DD, Zygmunt, PM, Högestätt, ED, Meng, ID, and Julius, D. (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427: 260-265.
Prescott, E.D. and Julius, D. (2003) A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300: 1284-1288.
Jordt, S-E. and Julius, D. (2002) Molecular basis of species-specific sensitivity to "hot" 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 416:52-59
Hollopeter. G., Jantzen, H-M., Vincent, D., Li, G., England, L., Ramakrishnan, V., Yang, R-B., Nurden, P., Nurden, A., Julius, D. and Conley, P.B., (2001) Molecular identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409: 202-207.
Julius D, Basbaum AI. Molecular mechanisms of nociception. (2001) Nature 413: 203-10. |
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