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The Journal of Neuroscience, April 27, 2005, 25(17):4319-4329; doi:10.1523/JNEUROSCI.5200-04.2005

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Cellular/Molecular
Activation of Protease-Activated Receptor-1 Triggers Astrogliosis after Brain Injury

Olivier Nicole,^1,3 Anna Goldshmidt,¹ Cecily E. Hamill,¹ Scott D. Sorensen,¹ Aristide Sastre,¹ Polina Lyuboslavsky,¹ John R. Hepler,¹ Robert J. McKeon,² and Stephen F. Traynelis¹

Departments of ¹Pharmacology and ²Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, and ³Université de Caen, Unité Mixte de Recherche-Centre National de la Recherche Scientifique 6185, 14074 Caen Cedex, France

We have studied the involvement of the thrombin receptor [protease-activated receptor-1 (PAR-1)] in astrogliosis, because extravasation of PAR-1 activators, such as thrombin, into brain parenchyma can occur after blood-brain barrier breakdown in a number of CNS disorders. PAR1^-/- animals show a reduced astrocytic response to cortical stab wound, suggesting that PAR-1 activation plays a key role in astrogliosis associated with glial scar formation after brain injury. This interpretation is supported by the finding that the selective activation of PAR-1 in vivo induces astrogliosis. The mechanisms by which PAR-1 stimulates glial proliferation appear to be related to the ability of PAR-1 receptor signaling to induce sustained extracellular receptor kinase (ERK) activation. In contrast to the transient activation of ERK by cytokines and growth factors, PAR-1 stimulation induces a sustained ERK activation through its coupling to multiple G-protein-linked signaling pathways, including Rho kinase. This sustained ERK activation appears to regulate astrocytic cyclin D1 levels and astrocyte proliferation in vitro and in vivo. We propose that this PAR-1-mediated mechanism underlying astrocyte proliferation will operate whenever there is sufficient injury-induced blood-brain barrier breakdown to allow extravasation of PAR-1 activators.

Key words: protease receptor; thrombin; astrogliosis; trauma; MAP kinase; G-protein

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Received July 30, 2004; revised March 18, 2005; accepted March 18, 2005.

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