TY - JOUR
T1 - Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1
AU - Mannaioni, Guido
AU - Orr, Anna G.
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, C. Justin
AU - Yepes, Manuel
AU - Hepler, John R.
AU - Traynelis, Stephen F.
PY - 2008/7/18
Y1 - 2008/7/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=50649100200&partnerID=8YFLogxK
U2 - 10.1074/jbc.M803015200
DO - 10.1074/jbc.M803015200
M3 - Article
C2 - 18474593
AN - SCOPUS:50649100200
SN - 0021-9258
VL - 283
SP - 20600
EP - 20611
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -