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J. Biol. Chem., Vol. 283, Issue 29, 20600-20611, July 18, 2008

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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^¶, C. Justin Lee^||, Manuel Yepes^**, John R. Hepler, and Stephen F. Traynelis¹

From the Dipartimento di Farmacologia, Università degli Studi di Firenze, 50139 Firenze, Italy, Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, ^¶Agensys Inc., Santa Monica, California 90404, ^||Korea Institute of Science and Technology, Seoul 136-791, Korea, and ^**Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322

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 -amino-3-hydroxy-5-methyl-4-isoxazole propionate- or -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 [Ca²⁺]_i in astrocytes and potentiate NMDA receptor synaptic currents in CA1 pyramidal neurons.

Received for publication, April 18, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS039419 (to S. F. T.) and NS049478 (to M. Y.). This work was also supported by National Research Service Award Grants NS054515 (to A. G. O.), NS530062 (to C. E. H.), and NS43875 (to C. J. L.), the National Alliance for Research on Schizophrenia and Depression (to S. F. T. and G. M.), and the Ente Cassa di Risparmio di Firenze, Italy (to G. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, 5062 Rollins Research Center, 1510 Clifton Rd., Emory University, Atlanta, GA 30322. Tel.: 404-727-0357; Fax: 404-313-0365; E-mail: strayne{at}emory.edu.

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