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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
Calcium signaling
From: Clapham, D.E., et al.Nat. Rev. Neurosci. 2, 387-396 (2001).
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)
Capacitative (store operated) Ca2+ entry (Putney)
From: Putney, J.W., Jr. Cell Calcium 11, 611-624 (1990).
Calcium Release Activated Calcium current (ICRAC)
From: Hoth, M. & Penner, R. Nature 355, 353-356 (1992).
TRP channels and capacitative calcium entry
From: Zhu, X., et al. Cell 85, 661-671 (1996).
From: Vaca, L., et al. Am. J. Physiol. 267 C1501-C1505 (1994).
+thapsigargin
ICRAC and TRP channels
ICRAC TRPCa2+ selective Non selective
cation channel
Inwardly rectifying Outwardly rectifying
Very small single channel conductance
Measurable single channel conductance
Store depletion activates
Store depletion activates (sometimes)
Direct activation of TRP channels by the IP3 receptor
From: Kiselyov, K., et al. Nature 396, 478-482 (1998).
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
Thermosensation
HotCold
Capsaicin (chili pepper) sensitizes to warm temperature
Menthol sensitizes to cold temperature
Cloning of the capsaicin receptor
From: Caterina, M.J., et al. Nature 389, 816-824 (1997).
2:4 x 106 independent bacterial clones were divided into 144 pools.
Cloning of the cold menthol receptor: TRPM8
From: McKemy, D.D., et al. Nature 416, 52-58 (2002). From: Peier, A.M., et al. Cell 108, 705-715 (2002).
TRPV4 is a mechanosensor
From: Liedtke,W., et al. Cell 103, 525-535 (2000).
TRPV4 -/- mice have impaired osmoregulation and pressure sensation
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)
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
Some TRPM channels are also enzymes
From: Yamaguchi, H., et al. Mol. Cell 7, 1047-1057 (2001).
From: Fleig, A. & Penner, R. Trends Pharmacol. Sci. 25, 633-639 (2004).
Kinase Domain
From: Walder, R.Y., et al. Nat. Genet. 31, 171-174 (2002).
Hypomagnesemia, hypocalcemia, Seizures
Caused by impaired intestinal Mg2+ absorption abnormal renal Mg2+ excretion
Can be overcome by high-dose Mg2+ supplementation
The role of the TRP domain as a PIP2 interacting site
From: Rohacs, T., et al. Nature Neuroscience in press
Extended TRP superfamily
From: Montell, C., et al. Mol. Cell 9, 229-231 (2002). From: Clapham, D.E. Nature 426, 517-524 (2003).
Another cold receptor: ANKTM1 (TRPA1)
From: Story, G.M., et al. Cell 112, 819-829 (2003).
From: Jordt, S.E., et al. Nature 427, 260-265 (2004).
Mechano-sensitive channels and hearing
From: Frolenkov, G.I., et al. Nat. Rev. Genet. 5, 489-498 (2004).
http://peir.path.uab.edu/iplab/messages/598/467.html?1002303218
From: Wilson, P.D. N. Engl. J. Med. 350, 151-164 (2004).
From: Igarashi, P. & Somlo, S. J. Am. Soc. Nephrol. 13, 2384-2398 (2002).
Polycystic Kidney Disease