PARs in the stars: proteinase-activated receptors and astrocyte function. Focus on "Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways".

IN THE FIRMAMENT OF THE BRAIN, astrocytes have in the past been considered to be primarily passive, supportive bystanders in terms of maintaining an optimal environment for the function of neuronal elements. Now, however, it is accepted that astrocytes, the most numerous cell type within the central nervous system (CNS), are key multifunctional units that are in a constant dialogue with each other and with neighboring neurons and adjacent vasculature. This bidirectional communication between astrocytes and other cell types is facilitated by their processes that can enwrap synaptic terminals and also impinge on vascular arterioles. Via their interaction with capillary endothelial cells, the astrocytes are thought to play a key role in the formation and maintenance of the bloodbrain barrier (16, 19, 20). Not only are astrocytes a major source of neurotrophic factors and cytokines, which in the setting of injury can affect neuronal survival and apoptosis (23, 45), but the astrocytes themselves are equipped with an abundance of receptors for neurotransmitters and neuromodulators (15, 40), including glutamate, which is believed to communicate directly via “spillover” from the neuron to the astrocyte. One common theme of the signaling pathways triggered by the astrocyte ionotropic receptors, such as those for glutamate (GluRs; see Ref. 40 for references), or by G protein-coupled receptors (GPCRs), such as those that activate Gs and cAMP-driven processes (28) or Gq and inositide-specific phospholipase C , is an elevation of intracellular Ca2 , which in turn activates a variety of intracellular signaling processes (40). Of note is the ability of the GPCR agonist endothelin (for which mRNA is detected in glia) to stimulate inositide turnover (i.e., Ca2 signaling) and mitogenesis in astrocytes (26). Like endothelin, thrombin has long been known as a regulator of vascular contractility (i.e., for mobilizing intracellular Ca2 ) and mitogenesis. Because of the likelihood of thrombin access to astrocytes in the setting of CNS vascular injury, the impact of thrombin on astrocyte function has been of interest since the mid-1980s, when it was discovered that thrombin is a potent mitogen for astrocytes (34). In addition to regulating astrocyte proliferation, thrombin can reverse astrocyte stellation via a signaling pathway involving tyrosine kinase (14), enhance astrocyte nerve growth factor production (30), and protect astrocytes from cell death caused by hypoglycemia or oxidative stress. Of note, Perraud et al. (34) showed that trypsin, like thrombin, is mitogenic for astrocytes. Although initially the circulation was considered the potential physiological source of thrombin in the CNS, mRNA for thrombin as well as its activating enzyme, factor X, along with its inhibitors, antithrombin III and protease-nexin-1, have all been detected in rat brain; all the machinery needed to generate and regulate thrombin is potentially available to expose astrocytes to thrombin action within the CNS (5, 7, 8, 36, 38). In addition to its actions on astrocytes, thrombin also has effects on neural elements (5, 10). Only recently, however, have the cellular mechanisms of action of thrombin been clarified so as to provide an infrastructure for the work described in the study by Wang et al., the current article in focus (Ref. 42, see p. C1351 in this issue). Long recognized for its role in the coagulation cascade, thrombin is now known to regulate its target cells, such as platelets and endothelial cells, in part via activation of a GPCR (3, 17, 27, 32, 35, 41). The novel mechanism whereby thrombin activates its receptors involves the proteolytic unmasking of a cryptic NH2Address for reprint requests and other correspondence: M. D. Hollenberg, Diabetes/Endocrine, Mucosal Inflammation, Smooth Muscle and Cancer Biology Research Groups, Depts. of Pharmacology & Therapeutics and Medicine, Faculty of Medicine, Univ. of Calgary, Calgary, AB, Canada T2N 4N1 (E-mail: [email protected]). Am J Physiol Cell Physiol 283: C1347–C1350, 2002; 10.1152/ajpcell.00304.2002.