Activation of protease-activated receptor-1 triggers astrogliosis after brain injury

O. Nicole
Journal of Neuroscience. 2005-04-27; 25(17): 4319-4329
DOI: 10.1523/JNEUROSCI.5200-04.2005

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1. J Neurosci. 2005 Apr 27;25(17):4319-29.

Activation of protease-activated receptor-1 triggers astrogliosis after brain
injury.

Nicole O(1), Goldshmidt A, Hamill CE, Sorensen SD, Sastre A, Lyuboslavsky P,
Hepler JR, McKeon RJ, Traynelis SF.

Author information:
(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
PAR-1 activators.

DOI: 10.1523/JNEUROSCI.5200-04.2005
PMID: 15858058 [Indexed for MEDLINE]


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