Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines.
While protease-activated receptors (PARs) are known to mediate signaling events in CNS, contributing both to normal function and pathogenesis, the endogenous activators of CNS PARs are poorly characterized. In this study, we test the hypothesis that kallikreins (KLKs) represent an important pool of endogenous activators of CNS PARs. Specifically, KLK1 and KLK6 were examined for their ability to evoke intracellular Ca(2+) flux in a PAR-dependent fashion in NSC34 neurons and Neu7 astrocytes. Both KLKs were also examined for their ability to activate mitogen-activated protein kinases (extracellular signal-regulated kinases, C-Jun N-terminal kinases, and p38) and protein kinase B (AKT) intracellular signaling cascades. Cumulatively, these studies show that KLK6, but not KLK1, signals through PARs. KLK6 evoked intracellular Ca(2+) flux was mediated by PAR1 in neurons and both PAR1 and PAR2 in astrocytes. Importantly, both KLK1 and KLK6 altered the activation state of mitogen-activated protein kinases and AKT, suggestive of important roles for each in CNS neuron and glial differentiation, and survival. The cellular specificity of CNS-KLK activity was underscored by observations that both proteases promoted AKT activation in astrocytes, but inhibited such signaling in neurons. PAR1 and bradykinin receptor inhibitors were used to demonstrate that KLK1-mediated activation of extracellular signal-regulated kinases in neurons occurred in a non-PAR, bradykinin 2 (B2) receptor-dependent fashion, while similar signaling by KLK6 was mediated by the combined activation of PAR1 and B2. Cumulatively results indicate KLK6, but not KLK1 is an activator of CNS PARs, and that both KLKs are poised to signal in a B2 receptor-dependent fashion to regulate multiple signal transduction pathways relevant to CNS physiologic function and dysfunction.
Vandell
Alexander G
AG
Molecular Neuroscience Program, Mayo Medical and Graduate School, Rochester, Minnesota 55905, USA.
Larson
Nadya
N
Laxmikanthan
Gurunathan
G
Panos
Michael
M
Blaber
Sachiko I
SI
Blaber
Michael
M
Scarisbrick
Isobel A
IA
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism; D007610:Kallikreins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D020840:Tissue Kallikreins / Q000378:metabolism*
D044462:Receptors, Proteinase-Activated; D007610:Kallikreins; C491223:Prss18 protein, mouse; D020840:Tissue Kallikreins; D002118:Calcium
J Neurosci. 2001 Jun 15;21(12):4336-47
11404419
J Neurotrauma. 2000 Dec;17(12):1191-203
11186232
J Cereb Blood Flow Metab. 2003 Apr;23(4):441-8
12679721
Adv Exp Med Biol. 1990;265:169-78
2198770
Biol Chem. 2001 Jan;382(1):77-89
11258677
Immunopharmacology. 1996 May;32(1-3):39-47
8796264
J Cell Biol. 1992 Jul;118(2):411-9
1321160
J Neurochem. 2000 May;74(5):1895-902
10800932
Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10300-4
7524091
Nat Med. 2000 Feb;6(2):151-8
10655102
J Neurochem. 2002 Feb;80(4):655-66
11841573
Mol Pharmacol. 2007 Sep;72(3):653-64
17596374
Biochemistry. 2002 Jan 29;41(4):1165-73
11802715
Biol Chem. 2007 Nov;388(11):1215-25
17976015
J Biol Chem. 2002 Jul 5;277(27):24562-70
11983703
J Biol Chem. 2007 Nov 2;282(44):31852-64
17823117
J Neurochem. 2007 Jul;102(1):65-76
17490439
J Neurosurg. 1997 Jul;87(1):73-8
9202268
J Neurosci. 1997 Jan 15;17(2):543-52
8987777
FASEB J. 2004 May;18(7):920-2
15033932
J Neurosci. 2003 Jul 2;23(13):5877-86
12843292
J Neurosci. 2000 Jun 15;20(12):4582-95
10844028
Exp Neurol. 2004 Jul;188(1):94-103
15191806
J Biol Chem. 2006 Feb 10;281(6):3116-26
16321973
J Comp Neurol. 2001 Mar 12;431(3):347-61
11170010
Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2264-9
10681455
Glia. 2004 Nov 1;48(2):91-101
15378660
Eur J Pharmacol. 1996 Jul 25;308(3):335-41
8858309
Neurosci Lett. 2002 Aug 30;329(2):181-4
12165407
Glia. 2002 Jan;37(1):53-63
11746783
N Engl J Med. 1979 Jun 7;300(23):1289-94
220534
J Neurosci Res. 2004 Jan 15;75(2):273-9
14705148
Neuroscience. 1998 Sep;86(1):279-90
9692761
J Cereb Blood Flow Metab. 2002 Apr;22(4):404-10
11919511
Nat Rev Cancer. 2004 Nov;4(11):876-90
15516960
Brain. 2002 Jun;125(Pt 6):1283-96
12023317
Learn Mem. 2003 Jan-Feb;10(1):26-39
12551961
Neurobiol Learn Mem. 2007 Oct;88(3):295-304
17544303
J Neurotrauma. 2005 Apr;22(4):491-500
15853465
J Exp Med. 2006 Feb 20;203(2):425-35
16476770
Neurobiol Aging. 1995 Jul-Aug;16(4):557-62
8544905
Hypertension. 2004 Feb;43(2):452-9
14698996
Hypertension. 2003 Mar;41(3):611-7
12623967
Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H1244-50
16272198
Brain Res. 1995 Aug 21;689(2):207-23
7583324
Biol Chem. 2008 Jun;389(6):739-45
18627300
Proteins. 2005 Mar 1;58(4):802-14
15651049
Glia. 2000 May;30(3):219-30
10756072
J Biol Chem. 2006 Oct 27;281(43):32095-112
16885167
J Neurochem. 1997 Nov;69(5):1890-6
9349532
J Neurosci. 1997 Nov 1;17(21):8156-68
9334391
J Neurosci. 1995 Apr;15(4):2906-19
7722637
J Biol Chem. 1997 Oct 3;272(40):25135-42
9312124
Neuropharmacology. 2006 May;50(6):714-25
16430928
Neurosci Res. 2006 Jan;54(1):15-23
16256233
Trends Neurosci. 1988 Dec;11(12):541-4
2471310
J Neurotrauma. 1993 Summer;10(2):167-79
7692071
Am J Physiol Cell Physiol. 2002 Nov;283(5):C1351-64
12372796
J Neurochem. 2004 Dec;91(6):1439-49
15584920
Stroke. 2002 Dec;33(12):3012-8
12468805
Nat Med. 2001 Jul;7(7):821-6
11433347
Brain Res Mol Brain Res. 2004 Jul 26;126(2):129-36
15249136
J Neuroimmunol. 2006 Sep;178(1-2):167-76
16824622
J Biol Chem. 2006 Mar 24;281(12):7927-36
16410250
Front Biosci. 2006 May 01;11:1323-7
16368519
J Neurotrauma. 2003 Sep;20(9):841-51
14577862
Mol Pharmacol. 2003 Nov;64(5):1199-209
14573770
Biol Chem. 2001 Jan;382(1):5-14
11258672
J Biol Chem. 1984 Jul 10;259(13):8522-8
6564130
Eur J Neurosci. 2006 Sep;24(5):1457-69
16987227
Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H948-58
16183725
Biochem J. 2007 Jan 1;401(1):65-78
16942465
Clin Biochem. 2002 May;35(3):225-31
12074831
J Immunol. 2003 Mar 1;170(5):2638-46
12594292
Curr Opin Neurobiol. 2001 Jun;11(3):297-305
11399427
Stroke. 2001 Sep;32(9):2164-9
11546912
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13019-24
14559973
J Neurobiol. 2001 Aug;48(2):87-100
11438939
J Immunol. 2007 Oct 15;179(8):5493-503
17911636
J Neurosci. 2005 Apr 27;25(17):4319-29
15858058
Cell Tissue Res. 2005 Mar;319(3):359-66
15726426
J Cereb Blood Flow Metab. 2005 Aug;25(8):978-89
15815587
Endocr Rev. 2005 Feb;26(1):1-43
15689571
Biol Chem. 2006 Jun;387(6):817-24
16800746