TRPC channel-mediated neuroprotection by PDGF involves Pyk2/ERK/CREB pathway.
Platelet-derived growth factor-BB (PDGF) has been reported to provide tropic support for neurons in the central nervous system. The protective role of PDGF on dopaminergic neurons, especially in the context of HIV-associated dementia (HAD), however, remains largely unknown. Here, we show that exogenous PDGF was neuroprotective against toxicity induced by HIV-1 Tat in primary midbrain neurons. Furthermore, we report the involvement of transient receptor potential canonical (TRPC) channels in PDGF-mediated neuroprotection. TRPC channels are Ca(2+)-permeable, nonselective cation channels with a variety of physiological functions. Blocking TRPC channels with either a blocker or short-interfering RNAs (specific for TRPC 5 and 6) in primary neurons resulted in suppression of both PDGF-mediated neuroprotection as well as elevations in intracellular Ca(2+). PDGF-mediated neuroprotection involved parallel but distinct ERK/CREB and PI3K/Akt pathways. TRPC channel blocking also resulted in suppression of PDGF-induced Pyk2/ERK/CREB activation, but not Akt activation. Relevance of these findings in vivo was further corroborated by intrastriatal injections of PDGF and HIV-1 Tat in mice. Administration of PDGF was able to rescue the dopaminergic neurons in the substantia nigra from Tat-induced neurotoxicity. This effect was attenuated by pre-treatment of mice with the TRP blocker, thus underscoring the novel role of TRPC channels in the neuroprotection mediated by PDGF.
Yao
H
H
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Peng
F
F
Fan
Y
Y
Zhu
X
X
Hu
G
G
Buch
S J
SJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D010982:Platelet-Derived Growth Factor; D050052:TRPC Cation Channels; D054322:tat Gene Products, Human Immunodeficiency Virus; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium
J Interferon Cytokine Res. 2002 May;22(5):517-26
12060490
Pflugers Arch. 2007 Nov;455(2):187-200
17486362
Nat Med. 2008 Jul;14(7):738-47
18542050
Neuroreport. 2002 Dec 20;13(18):2483-6
12499853
J Biol Chem. 2000 Feb 11;275(6):4159-65
10660577
Eur J Neurosci. 2006 Aug;24(3):732-8
16930403
Neurotox Res. 2005 Oct;8(1-2):51-61
16260385
Biochem J. 1990 Oct 15;271(2):515-22
2173565
J Biol Chem. 2009 Mar 20;284(12):8054-63
19106110
Nature. 2003 Dec 4;426(6966):517-24
14654832
J Neurosci. 2006 Apr 5;26(14):3798-804
16597733
J Biol Chem. 2005 Jan 21;280(3):2132-40
15542611
J Neurosci Res. 2006 Aug 1;84(2):268-77
16752416
J Neurovirol. 2008 Jan;14(1):62-72
18300076
Neurosci Lett. 2006 Jul 10;402(1-2):35-9
16635549
Pharmacol Rev. 2005 Dec;57(4):427-50
16382100
Stem Cells. 2006 Dec;24(12):2637-48
16916926
Cell Signal. 2002 Aug;14(8):649-54
12020764
Ann N Y Acad Sci. 2007 Dec;1122:144-54
18077570
Annu Rev Physiol. 2006;68:619-47
16460286
Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8159-63
1654560
Nat Med. 2000 Dec;6(12):1380-7
11100124
J Neurochem. 2005 Feb;92(4):948-61
15686497
J Neurochem. 2003 Jun;85(5):1299-311
12753088
Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14092-7
16174730
Trends Neurosci. 1999 Jun;22(6):257-63
10354603
Nat Rev Neurosci. 2001 Jun;2(6):387-96
11389472
Brain Res. 2006 Jul 12;1099(1):141-9
16765919
Biol Res. 2008;41(2):183-95
18949136
J Pharmacol Sci. 2005 Jul;98(3):212-8
16006741
Nat Neurosci. 2007 May;10(5):559-67
17396124
Mol Pharmacol. 2003 Sep;64(3):773-82
12920215
Exp Neurol. 2004 Mar;186(1):89-98
14980813
J Biol Chem. 1998 Jan 2;273(1):133-42
9417057
J Neurosci. 2009 Feb 11;29(6):1657-69
19211873
Prog Neurobiol. 2008 Aug;85(4):407-32
18586376
Cell Death Differ. 2005 Oct;12(10):1329-43
15905876
Eur J Neurosci. 2008 Oct;28(7):1255-64
18973553
Exp Brain Res. 1995;105(1):111-22
7589308
Nat Cell Biol. 2000 Sep;2(9):574-81
10980697
J Psychopharmacol. 2000;14(3):222-7
11106300
Genes Dev. 2008 May 15;22(10):1276-312
18483217
Cell. 2002 Mar 8;108(5):595-8
11893331