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.

Transient Receptor Potential Canonical 3 (TRPC3) Mediates Thrombin-Induced Astrocyte Activation and Upregulates Its Own Expression in Cortical Astrocytes

“…Body temperature was held at 37°C with a thermostatic heating pad. The head was fixed to a mouse stereotaxic frame, a burr hole was drilled, and a 30-gauge injection needle was lowered into the right cortex (anterior, 0.0 mm; lateral, 2.0 mm; and ventral, 1.0 mm from bregma) (Nicole et al, 2005). Drug or PBS plus 0.1% lipid-free BSA was injected in a volume of 0.5 l over 5 min using a Hamilton syringe, and the needle was left in place for an additional 5 min.…”

“…In addition to these physiological functions, pathologically activated astrocytes-so-called "reactive astrocytes"-have been reported to show astrogliosis, which is clinically characterized as abnormal morphology and excessive proliferation of astrocytes (Sofroniew, 2009), and can be caused by brain injury (Nicole et al, 2005).…”

“…Reactive astrocytes treated with thrombin exhibit dynamic morphological changes (Suidan et al, 1997;Majumdar et al, 1998) that correlate with their excessive proliferation (Majumdar et al, 1998;Wang et al, 2002) and subsequent astrogliosis (Nicole et al, 2005). These responses are regulated by protease-activated receptor (PAR), a subtype of G-protein-coupled receptor, which is activated by thrombin (Coughlin, 2000).…”

Learning and memory deficits in mice lacking protease activated receptor-1

“…Upon activation, PAR1 couples to multiple heterotrimeric G-proteins, including Gα q/11 , Gα i/0 , and Gα 12/13 , and their respective intracellular signaling pathways. PAR1 is highly-expressed in the CNS in rodents and humans, with the highest levels of expression seen in astrocytes, as well as dopaminergic neurons in the ventral tegmental area (Weinstein et al, 1995;Niclou et al, 1998;Junge et al, 2004;Nicole et al, 2005). Notably, in adult animals, PAR1 is expressed at moderate to high levels in brain regions involved with emotional learning, including hippocampus and amygdala (Striggow et al, 2001).…”

“…Notably, in adult animals, PAR1 is expressed at moderate to high levels in brain regions involved with emotional learning, including hippocampus and amygdala (Striggow et al, 2001). PAR1 has been extensively studied for its role in coagulation and hemostasis (Coughlin, 2000;Macfarlane et al, 2001), as well as in the survival of neurons following ischemic, traumatic, or neurotoxic insults (Gingrich & Traynelis, 2000a;Shibata et al, 2001;Riewald et al, 2002;Suo et al, 2002;Cheng et al, 2003;Junge et al, 2003;Xi et al, 2003;Guo et al, 2004;Olson et al, 2004;Hamill et al, 2005;Nicole et al, 2005). Surprisingly little, however, is known about PAR1's roles in normal brain function.…”