title: Activation of protease-activated receptor-1 triggers astrogliosis after brain injury.
abstract: 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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. onicole@neuro.unicaen.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Nicole
authors.forename: Anna
authors.initials: A
authors.lastname: Goldshmidt
authors.forename: Cecily E
authors.initials: CE
authors.lastname: Hamill
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sorensen
authors.forename: Aristide
authors.initials: A
authors.lastname: Sastre
authors.forename: Polina
authors.initials: P
authors.lastname: Lyuboslavsky
authors.forename: John R
authors.initials: JR
authors.lastname: Hepler
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McKeon
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000473:pathology*; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001930:Brain Injuries / Q000473:pathology* / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D005576:Colforsin / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology*; D007150:Immunohistochemistry / Q000379:methods; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000577:Amides; D002070:Butadienes; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009570:Nitriles; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D011725:Pyridines; D012333:RNA, Messenger; D044463:Receptor, PAR-1; C113580:U 0126; D019938:Cyclin D1; C108830:Y 27632; D005576:Colforsin; D020930:MAP Kinase Kinase Kinases; D013917:Thrombin; D001973:Bromodeoxyuridine