Four different types of protease‐activated receptors are widely expressed in the brain and are up‐regulated in hippocampus by severe ischemia

Abstract

A variety of extracellular serine proteases are expressed in the central nervous system or might permeate the blood-brain barrier under pathological conditions. However, their intracerebral targets and physiological functions are largely unknown. Here, we show that four distinct subtypes of protease-activated receptors (PARs) are abundantly expressed in the adult rat brain and in organotypic hippocampal slice cultures. PAR-1 expression was significant in the hippocampus, cortex and amygdala. Highest densities of PAR-2 and PAR-3 were observed in hippocampus, cortex, amygdala, thalamus, hypothalamus and striatum. Apart from the striatum, a similar localization was found for PAR-4. Within the hippocampal formation, each PAR subtype was predominantly localized in the pyramidal cell layers. Additionally, we identified PAR-2 in mossy fibers between dentate gyrus and CA3, PAR-3 in the subiculum and PAR-4 in CA3 and in mossy fibres as well as in the stratum lacunosum moleculare. After exposing hippocampal slice cultures to a severe experimental ischemia (oxygen-glucose deprivation), the expression of PARs 1-3 was up-regulated with subtype-specific kinetics. The localization of PARs in brain regions particularly vulnerable to ischemic insults as well as distinct alterations in the expression pattern after experimental ischemia support the notion of an important role of extracellular serine proteases and PARs in cerebral ischemia.

Deficiency of PAR4 Attenuates Cerebral Ischemia/Reperfusion Injury in Mice

“…It was shown that after transient focal ischemia in the rat brain, PAR1 mRNA was found to be downregulated. However, PAR3 and PAR4 mRNA levels were increased (Rohatgi et al, 2004) and there was enhanced PAR4 labeling in the penumbra (Henrich-Noack et al, 2006;Striggow et al, 2001). The effects of thrombin were also shown in other experimental ischemic models.…”

“…The activation of PAR1, PAR3, and PAR4 has been intensively investigated in platelets (Coughlin, 2000;Ishihara et al, 1997;Kahn et al, 1998;Molino et al, 1997). In addition to platelets, PARs are also found to be widely expressed in the brain (Striggow et al, 2001;Wang et al, 2002). PAR4 protein is found on dendrites of the hippocampus and all cortical layers (Striggow et al, 2001).…”

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

“…However, since NMDA receptor function has been shown to be normal in PAR1 −/− animals Lee et al, 2007), another interpretation of the data is that potentiation of NMDA receptors by activation of PAR1 is important for learning and memory. Furthermore, both PAR1 (Striggow et al, 2001), and NMDA receptor subunits (Ishii et al, 1993) are highly expressed in brain regions involved with emotional learning, including hippocampus and amygdala. These results it well with suggestions that serine proteases can impact learning (Baranes et al, 1998;Pawlak et al, 2002;Nagai et al, 2004Nagai et al, ,2006Pang et al, 2004;Pawlak et al, 2005), and may suggest that PAR1 is a substrate at which serine proteases such as plasmin exert their actions.…”

“…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). 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).…”

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

“…These peptides have been used as selective agonists for studying the function of PARs in vivo and in vitro. Although PARs were first discovered in a search for the receptors mediating the hormone-like effects of thrombin on platelets, subsequent studies showed their widespread expression in different cell types in the gastrointestinal, cardiovascular, respiratory, genitourinary, and central, and peripheral nervous systems (3)(4)(5)(6)(7)(8)(9). All four PARs have been shown to be expressed in the CNS, while their activating proteases can either be produced within the brain or originate from extravasated plasma during inflammatory processes (10).…”