Phospholipase D1-promoted release of tissue plasminogen activator facilitates neurite outgrowth.
Temporal lobe epilepsy (TLE) is the most common form of epilepsy, affecting approximately 1-2% of the population. Seizure events resulting from TLE are characterized by aberrant hippocampal mossy fiber sprouting and plastic responses that affect brain function. Seizure susceptibility is modulated by the enzyme tissue plasminogen activator (tPA), the normal physiological role of which includes promotion of synaptic reorganization in the mossy fiber pathway by initiating a proteolytic cascade that cleaves extracellular matrix components and influences neurite extension. tPA is concentrated at and selectively secreted from growth cones during excitatory events. However, the mechanisms underlying tPA release during seizure-induced synaptogenesis are not well understood. We examine here potential roles for the signaling enzyme phospholipase D1 (PLD1), which promotes regulated exocytosis in non-CNS cell types, and which we previously demonstrated increases in expression in hippocampal neurons during seizure-induced mossy fiber sprouting. We now show that overexpression of wild-type PLD1 in cultured neurons promotes tPA release and tPA-dependent neurite extension, whereas overexpression of an inactive PLD1 allele or pharmacological inhibition of PLD1 inhibits tPA release. Similarly, viral delivery of wild-type PLD1 into the hippocampus facilitates tPA secretion and mossy fiber sprouting in a seizure-inducing model, whereas the inactive PLD1 allele inhibits tPA release and elicits blunted and abnormal mossy fiber extension similar to that observed for tPA-/- mice. Together, these findings secretion and thus mossy fiber extension in the setting of elevated suggest that PLD1 functions endogenously to regulate tPA-/- neuronal stimulation, such as that seen in TLE.
Zhang
Yan
Y
Program in Molecular and Cellular Pharmacology, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, New York 11794, USA.
Kanaho
Yasunori
Y
Frohman
Michael A
MA
Tsirka
Stella E
SE
D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology; D002478:Cells, Cultured / Q000201:enzymology / Q000648:ultrastructure; D003292:Convulsants / Q000633:toxicity; D004833:Epilepsy, Temporal Lobe / Q000503:physiopathology*; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000254:growth & development / Q000648:ultrastructure; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010739:Phospholipase D / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012845:Sindbis Virus / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D003292:Convulsants; D011993:Recombinant Fusion Proteins; D010739:Phospholipase D; C106801:phospholipase D1; D010959:Tissue Plasminogen Activator; D007608:Kainic Acid
Neurosci Lett. 1999 Apr 16;265(2):127-30
10327185
Biochim Biophys Acta. 1999 Jul 30;1439(2):175-86
10425394
J Pharmacol Exp Ther. 1999 Dec;291(3):1188-95
10565841
J Cell Physiol. 2000 Jan;182(1):77-87
10567919
Cell. 1999 Nov 24;99(5):521-32
10589680
Biochem J. 2000 Feb 1;345 Pt 3:401-15
10642495
J Cell Biol. 2000 Mar 20;148(6):1295-304
10725341
J Biol Chem. 2000 Aug 4;275(31):23911-8
10801816
Biochim Biophys Acta. 2000 Jun 2;1497(1):103-14
10838164
Neuroscience. 2000;98(3):407-27
10869836
J Clin Invest. 2000 Oct;106(7):907-15
11018079
Learn Mem. 2000 Nov-Dec;7(6):433-41
11112802
Nat Med. 2001 Jan;7(1):59-64
11135617
EMBO J. 2001 May 15;20(10):2424-34
11350931
J Neurophysiol. 2001 Aug;86(2):1037-42
11495971
Neuropharmacology. 2001 Sep;41(3):384-91
11522330
J Neurochem. 2001 Sep;78(5):1044-53
11553678
Neurochem Res. 2001 Oct;26(10):1151-5
11700958
Cell Mol Life Sci. 2001 Oct;58(11):1674-87
11706993
J Biol Chem. 2002 Feb 22;277(8):5823-31
11744730
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15300-5
11752468
J Neurosci. 2002 Mar 15;22(6):2125-34
11896152
J Immunol. 2002 Jun 1;168(11):5682-9
12023367
J Neurosci. 2002 Aug 1;22(15):6650-8
12151544
J Neurochem. 2002 Sep;82(6):1406-15
12354288
J Cell Biol. 2002 Oct 14;159(1):79-89
12379803
Science. 2003 Mar 7;299(5612):1585-8
12624270
J Neurosci. 2003 Apr 15;23(8):3234-42
12716930
Mol Biol Cell. 2004 Mar;15(3):1024-30
14718562
Glia. 2004 Apr 1;46(1):74-83
14999815
Biochem Cell Biol. 2004 Feb;82(1):225-53
15052340
J Biol Chem. 2004 Jun 25;279(26):27534-41
15087463
J Comp Neurol. 1991 Jun 15;308(3):409-17
1865008
Dev Biol. 1985 Jul;110(1):91-101
2989045
Neuroscience. 1987 Mar;20(3):739-48
3037433
J Neurosci Res. 1988 Oct-Dec;21(2-4):420-5
3145983
Science. 1981 Sep 25;213(4515):1532-4
7197054
Nature. 1995 Sep 28;377(6547):340-4
7566088
Neurosci Lett. 1994 Oct 24;180(2):123-6
7700563
J Neurochem. 1993 Oct;61(4):1569-72
8104235
Brain Res. 1993 Oct 29;626(1-2):106-16
8281421
Nature. 1993 Feb 4;361(6411):453-7
8429885
J Neurosci. 1996 Apr 1;16(7):2220-5
8601802
Br J Pharmacol. 1996 Jun;118(4):1035-43
8799579
Biochem Pharmacol. 1996 Nov 8;52(9):1399-405
8937450
Adv Neurol. 1997;72:25-34
8993681
J Biol Chem. 1997 Jan 17;272(3):1976-82
8999889
Curr Opin Neurol. 1997 Apr;10(2):103-9
9146991
J Cell Biol. 1997 Aug 11;138(3):495-504
9245781
Cold Spring Harb Symp Quant Biol. 1996;61:739-45
9246499
Biochem J. 1997 Sep 15;326 ( Pt 3):745-53
9307024
Neurochem Res. 1997 Oct;22(10):1215-22
9342725
Curr Biol. 1998 Jan 1;8(1):19-25
9427623
Neuroscience. 1998 Mar;83(1):251-8
9466414
Mol Biol Cell. 1998 Sep;9(9):2463-76
9725906
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12989-94
9789028
Neuron. 1998 Oct;21(4):813-25
9808467
Brain Res. 1999 Jan 23;816(2):337-49
9878817