Molecular Pharmacology
Research
The Molecular Pharmacology Laboratory focuses on the molecular pharmacology of receptors and ion channels involved in pain sensation. In particular, we study a group of thermosensitive “Transient Receptor Potential” (TRP) ion channels that sense heat, cold and painful stimuli.
Hot chilies spice-up our food but they can also cause excruciating pain if they get into a cut or onto sensitive tissues. This pain is caused by the opening of the TRPV1 ion channel on the affected sensory nerves and initiating action potentials in them. TRPV1 is also activated by noxious heat and by low pH solutions and it is a marker for pain-sensing or “nociceptive” nerves. The “polymodal” activation of TRPV1 makes it a major target for drug companies trying to make new types of pain-killing drugs. While working for Novartis, Professor McIntyre's group was the first to show that antagonists of TRPV1 are effective in reversing inflammatory and neuropathic hyperalgesia in experimental models [1]. They have since developed orally available TRPV1 antagonist which could prove to be effective in humans [2]. The TRPV1 ion channel is regulated at multiple levels. It expression on the surface of nerves is controlled by phosphorylation and probably also by interacting proteins, it ability to open in response to agonist is under feedback control by calcium-dependent mechanisms to either sensitize or desensitize the channel to activators (also involving phosphorylation). We are interested in understanding how this ion channel and its close homologue, TRPV4, is trafficked to the cell surface and how phosphorylation acts as a molecular switch to sensitize and desensitize these channels to agonists. We also use species differences to dissect important functional regions of the channel [3].
Working together with the group of Ardem Patapoutian in San Diego, we identified one novel and two “orphan” TRP channels. This exercise revealed the existence of the heat -activated TRPV3 [4] and the cold-activated TRPM8 [5] and TRPA1 (formerly anktm1) [6].
We are currently particularly interested in two areas: 1) desensitization and activation of the heat-activated ion channels, TRPV1 and TRPV4 and the cold-activated ion channels TRPM8 and TRPA1. We are currently studying the post-translational modification of TRPM8 and the molecular mechanisms controlling sensitization of this ion channel to agonists and thermal stimulation [7].
The laboratory also has broad interests in ion channel expression in mammalian cell systems for analysis of multi-subunit ion channel function.
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Key References
1. Culshaw AJ, Bevan S, Christiansen M, Copp P, Davis A, et al. 2006. J Med Chem 49: 471-4
2. Wotherspoon G, Fox A, McIntyre P, Colley S, Bevan S, Winter J. 2005. Neuroscience 135: 235-45
3. Fox A, Kaur S, Li B, Panesar M, Saha U, Davis, C, Dragoni, I, Colley, S, Ritchie, T, Bevan, S, Burgess, G, McIntyre, P. 2005. Br J Pharmacol 144: 889-99
4. Phillips E, Reeve A, Bevan S, McIntyre P. 2004. J Biol Chem 279: 17165-72
5. Walker KM, Urban L, Medhurst SJ, Patel S, Panesar M, et al. 2003. J Pharmacol Exp Ther 304: 56-62
6. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, et al. 2003. Cell 112: 819-29
7. Savidge J, Davis C, Shah K, Colley S, Phillips E, et al. 2002. Neuropharmacology 43: 450-6
8. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, et al. 2002. Science 296: 2046-9
9. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, et al. 2002. Cell 108: 705-15
10. McIntyre P, McLatchie LM, Chambers A, Phillips E, Clarke M, et al. 2001. Br J Pharmacol 132: 1084-94
11. Dragoni, I., Guida, E. & McIntyre, P. "The cold and menthol receptor TRPM8 contains a functionally important double cysteine motif" (2006), J Biol chem, 281, 37353-37360.
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