Activation of protease-activated receptor-1 triggers astrogliosis after brain injury
Journal of Neuroscience. 2005-04-27; 25(17): 4319-4329
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1. J Neurosci. 2005 Apr 27;25(17):4319-29.
Activation of protease-activated receptor-1 triggers astrogliosis after brain
Nicole O(1), Goldshmidt A, Hamill CE, Sorensen SD, Sastre A, Lyuboslavsky P,
Hepler JR, McKeon RJ, Traynelis SF.
(1)Department of Pharmacology, Emory University School of Medicine, Atlanta,
Georgia 30322, USA.
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
PMID: 15858058 [Indexed for MEDLINE]