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TRP channels

TRP channels. Tibor Rohacs. Calcium. Three major compartments: Intracellular: signaling ion, very low concentration (~ 100 nM) Extracellular: ~2.5 mM total, ~1.25 mM ionized Bones: hydroxyapatite crystals: Ca 10 (PO 4 ) 6 (OH) 2. Calcium signaling. GPCR-s: Angiotensin II

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TRP channels

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  1. TRP channels Tibor Rohacs

  2. Calcium Three major compartments: • Intracellular: signaling ion, very low concentration (~ 100 nM) • Extracellular: ~2.5 mM total, ~1.25 mM ionized • Bones: hydroxyapatite crystals: Ca10(PO4)6(OH)2

  3. Calcium signaling GPCR-s: Angiotensin II Acetylcholine (M1 M3) Adrenergic alpha-1 Thrombin Metabotropic GluR RTK-s EGF, NGF, BDNF etc Other factors Sperm  oocyte Light (invertebrates) From: Clapham, D.E., et al. Nat. Rev. Neurosci.2, 387-396 (2001).

  4. Capacitative (store operated) Ca2+ entry (Putney) From: Putney, J.W., Jr. Cell Calcium11, 611-624 (1990).

  5. Calcium Release Activated Calcium current (ICRAC) From: Hoth, M. & Penner, R. Nature355, 353-356 (1992).

  6. Invertebrate Phototransduction From: Minke, B. & Cook, B. Physiol Rev.82, 429-472 (2002).

  7. Transient Receptor Potential From: Minke, B. & Cook, B. Physiol Rev.82, 429-472 (2002).

  8. TRP channels and capacitative calcium entry +thapsigargin From: Vaca, L., et al. Am. J. Physiol.267 C1501-C1505 (1994). From: Zhu, X., et al. Cell85, 661-671 (1996).

  9. ICRAC and TRP channels

  10. Direct activation of TRP channels by the IP3 receptor From: Kiselyov, K., et al. Nature396, 478-482 (1998).

  11. DAG activation of TRPC3,6,7 From: Hofmann,T., et al. Nature397, 259-263 (1999).

  12. PIP2 inhibition of TRPL From: Estacion, M., et al. J. Physiol530, 1-19 (2001).

  13. The TRPC (Classical) family • Homologues of TRP and TRPL • Seven members TRPC1-7 • Are activated upon PLC activation • Store Operated • DAG  TRPC3,6,7 • IP3 receptor  direct interaction • PIP2 inhibits TRPL channels, other TRPC-s are not tested yet • No general paradigm on how PLC activates these TRPC channels

  14. Thermosensation Capsaicin (chili pepper) sensitizes to warm temperature Menthol sensitizes to cold temperature Hot Cold

  15. Cloning of the capsaicin receptor 2:4 x 106 independent bacterial clones were divided into 144 pools. From: Caterina, M.J., et al. Nature389, 816-824 (1997).

  16. TRPV1 integrates pain producing stimuli From: Tominaga, M., et al. Neuron21, 531-543 (1998).

  17. TRPV1 KO mouse From: Caterina, M.J., et al. Science288, 306-313 (2000).

  18. Cloning of the cold menthol receptor: TRPM8 From: McKemy, D.D., et al. Nature416, 52-58 (2002). From: Peier, A.M., et al. Cell108, 705-715 (2002).

  19. Heat sensitive TRP channels From: Jordt, S.E., et al. Curr. Opin. Neurobiol.13, 487-492 (2003).

  20. TRPV4 is a mechanosensor TRPV4 -/- mice have impaired osmoregulation and pressure sensation From: Liedtke,W., et al. Cell103, 525-535 (2000).

  21. Epithelial calcium channels From: Hoenderop, J.G., et al. Physiol Rev.85, 373-422 (2005).

  22. TRPV5-6 Biophysical properties TRPV5 From: Hoenderop, J.G., et al. Physiol Rev.85, 373-422 (2005).

  23. The TRPV5 Knockout mouse From: Hoenderop, J.G., et al. J. Clin. Invest112, 1906-1914 (2003).

  24. The TRPV (Vanilloid) family • The first cloned member (1997): capsaicin receptor (TRPV1) ”heat” receptor, “chili pepper” • TRPV2-3 also temperature receptors • (insensitive to capsaicin) • TRPV4 osmosensor (also temperature sensitive) • TRPV5-6 Epithelial calcium transporters (only Ca2+ selective TRP-s)

  25. The TRPM (Melastain) family • Melastatin TRPM1  tumor suppressor • TRPM2  ADP ribose activated Ca2+ permeable channel • TRPM3 • TRPM4  Ca2+ activated non selective • TRPM5  taste tissues • TRPM6  Mg2+ homeostasis, disease !! • TRPM7  Mg2+ homeostasis, PIP2 activates • TRPM8  Cold receptor

  26. Some TRPM channels are also enzymes KinaseDomain From: Fleig, A. & Penner, R. Trends Pharmacol. Sci.25, 633-639 (2004). From: Yamaguchi, H., et al. Mol. Cell 7, 1047-1057 (2001).

  27. Hypomagnesemia, hypocalcemia, Seizures Caused by impaired intestinal Mg2+ absorption abnormal renal Mg2+ excretion Can be overcome by high-dose Mg2+ supplementation From: Walder, R.Y., et al. Nat. Genet.31, 171-174 (2002).

  28. From: Chubanov,V., et al. Proc. Natl. Acad. Sci. U. S. A101, 2894-2899 (2004).

  29. Is there anything common among the regulation of TRP channels ?

  30. From: Runnels, L.W., et al. Nat. Cell Biol.4, 329-336 (2002).

  31. TRPM8 From: Rohacs, T., et al. Nature Neuroscience in press

  32. The role of the TRP domain as a PIP2 interacting site From: Rohacs, T., et al. Nature Neuroscience in press

  33. Extended TRP superfamily From: Clapham, D.E. Nature426, 517-524 (2003). From: Montell, C.,et al. Mol. Cell9, 229-231 (2002).

  34. Another cold receptor: ANKTM1 (TRPA1) From: Story, G.M.,et al. Cell112, 819-829 (2003). From: Jordt, S.E., et al. Nature427, 260-265 (2004).

  35. Mechano-sensitive channels and hearing From: Frolenkov, G.I., et al. Nat. Rev. Genet.5, 489-498 (2004).

  36. SiRNA TRPA From: Corey, D.P., et al. Nature432, 723-730 (2004).

  37. Polycystic Kidney Disease http://peir.path.uab.edu/iplab/messages/598/467.html?1002303218 From: Igarashi, P. & Somlo, S. J. Am. Soc. Nephrol.13, 2384-2398 (2002). From: Wilson, P.D. N. Engl. J. Med.350, 151-164 (2004).

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