Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1

Guido Mannaioni, Anna G. Orr, Cecily E. Hamill, Hongjie Yuan, Katherine H. Pedone, Kelly L. McCoy, Rolando Berlinguer Palmini, Candice E. Junge, Changjoon Lee, Manuel Yepes, John R. Hepler, Stephen F. Traynelis

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Abstract

Protease-activated receptor-1 (PAR1) is activated by a number of serine proteases, including plasmin. Both PAR1 and plasminogen, the precursor of plasmin, are expressed in the central nervous system. In this study we examined the effects of plasmin in astrocyte and neuronal cultures as well as in hippocampal slices. We find that plasmin evokes an increase in both phosphoinositide hydrolysis (EC50 64 nM) and Fura-2/AM fluorescence (195 ± 6.7% above base line, EC50 65 nM) in cortical cultured murine astrocytes. Plasmin also activates extracellular signal-regulated kinase (ERK1/2) within cultured astrocytes. The plasmin-induced rise in intracellular Ca2+ concentration ([Ca2+]i) and the increase in phospho-ERK1/2 levels were diminished in PAR1-/- astrocytes and were blocked by 1 μM BMS-200261, a selective PAR1 antagonist. However, plasmin had no detectable effect on ERK1/2 or [Ca2+]i signaling in primary cultured hippocampal neurons or in CA1 pyramidal cells in hippocampal slices. Plasmin (100-200 nM) application potentiated the N-methyl-D-aspartate (NMDA) receptor-dependent component of miniature excitatory postsynaptic currents recorded from CA1 pyramidal neurons but had no effect on α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-or γ-aminobutyric acid receptor-mediated synaptic currents. Plasmin also increased NMDA-induced whole cell receptor currents recorded from CA1 pyramidal cells (2.5 ± 0.3-fold potentiation over control). This effect was blocked by BMS-200261 (1 μM; 1.02±0.09-fold potentiation over control). These data suggest that plasmin may serve as an endogenous PAR1 activator that can increase [Ca 2+]i in astrocytes and potentiate NMDA receptor synaptic currents in CA1 pyramidal neurons.

Original languageEnglish
Pages (from-to)20600-20611
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number29
DOIs
Publication statusPublished - 2008 Jul 18
Externally publishedYes

Fingerprint

PAR-1 Receptor
Fibrinolysin
N-Methyl-D-Aspartate Receptors
Neurons
Chemical activation
Astrocytes
Pyramidal Cells
Aminobutyrates
Isoxazoles
Neurotransmitter Receptor
Fura-2
Excitatory Postsynaptic Potentials
Plasminogen
Mitogen-Activated Protein Kinase 1
Extracellular Signal-Regulated MAP Kinases
Propionates
Neurology
Serine Proteases
N-Methylaspartate
Phosphatidylinositols

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1. / Mannaioni, Guido; Orr, Anna G.; Hamill, Cecily E.; Yuan, Hongjie; Pedone, Katherine H.; McCoy, Kelly L.; Palmini, Rolando Berlinguer; Junge, Candice E.; Lee, Changjoon; Yepes, Manuel; Hepler, John R.; Traynelis, Stephen F.

In: Journal of Biological Chemistry, Vol. 283, No. 29, 18.07.2008, p. 20600-20611.

Research output: Contribution to journalArticle

Mannaioni, G, Orr, AG, Hamill, CE, Yuan, H, Pedone, KH, McCoy, KL, Palmini, RB, Junge, CE, Lee, C, Yepes, M, Hepler, JR & Traynelis, SF 2008, 'Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1', Journal of Biological Chemistry, vol. 283, no. 29, pp. 20600-20611. https://doi.org/10.1074/jbc.M803015200
Mannaioni, Guido ; Orr, Anna G. ; Hamill, Cecily E. ; Yuan, Hongjie ; Pedone, Katherine H. ; McCoy, Kelly L. ; Palmini, Rolando Berlinguer ; Junge, Candice E. ; Lee, Changjoon ; Yepes, Manuel ; Hepler, John R. ; Traynelis, Stephen F. / Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 29. pp. 20600-20611.
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AU - Hamill, Cecily E.

AU - Yuan, Hongjie

AU - Pedone, Katherine H.

AU - McCoy, Kelly L.

AU - Palmini, Rolando Berlinguer

AU - Junge, Candice E.

AU - Lee, Changjoon

AU - Yepes, Manuel

AU - Hepler, John R.

AU - Traynelis, Stephen F.

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