Trypsin and trypsin-like proteases in the brain: Proteolysis and cellular functions

Abstract

Several serine proteases including thrombin, tissue-type plasminogen activator and urokinase-type plasminogen activator have been well characterized in the brain. In this article, we review the brain-related trypsin and trypsin-like serine proteases. Accumulating evidence demonstrates that trypsin and trypsin-like serine proteases play very important roles in neural development, plasticity, neurodegeneration and neuroregeneration in the brain. Neuropsin is able to hydrolyze the extracellular matrix components by its active site serine, and regulates learning and memory in normal brain. The mutant neurotrypsin contributes to mental retardation in children. Neurosin seems to be involved in the pathogenesis of neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease or multiple sclerosis. Although mesotrypsin/trypsin IV is also implicated in neurodegeneration, its functional significance still remains largely unknown. Particularly, mesotrypsin/trypsin IV, P22 and neurosin exert their physiological and pathological functions through activation of certain protease-activated receptors (PARs). In the brain, the presence of serpins controls the activity of serine proteases. Therefore, understanding the interaction among brain trypsin, serpins and PARs will provide invaluable tools for regulating normal brain functions and for the clinical treatment of neural disorders.

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

“…Proteolysis of ABCC1 by serine proteases is inhibited by GSH. 49 Given the potential role of cysteine and serine proteases after TBI, [50][51][52] it is tempting to speculate that protease activation after TBI may modulate ABCB1 and/or ABCC1 transporter expression and/or function. Further study including identification of these peptide bands using mass spectroscopy and functional assays ex vivo appear justified.…”

Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

“…In neurons, PAR2 is believed to act as a regulator of proteinase activity through a feedback mechanism that controls release of proteinases to regulate extracellular processes that are involved in synaptic plasticity (Lohman et al, 2008;Wang et al, 2008). Numerous studies have demonstrated that in hippocampus PAR2 and proteases are involved in synaptogenesis, long-term potentiation and depression and may contribute to excitotoxicity through cleavage of the NR1 subunit of NMDA glutamate receptors (Hoffman et al, 1998;Nicole et al, 2001;Qian et al, 1993;Scarisbrick et al, 2001;Tomimatsu et al, 2002;Yepes et al, 2002).…”

“…When in surveillance mode ramified microglia constantly sense the environment by sampling of the extracellular space with rapidly and constantly moving processes in order to detect cellular debris or pathogens prior to their removal by the microglia once they are activated and in phagocytitic mode (Kettenmann et al, 2011;Nimmerjahn et al, 2005). Such activity depends on a complex interaction of proteinases and cellular adhesion molecules and occurs in the immediate environment of the cellular process due to low concentrations of the proteinase and tight control of the proteinase by irreversibly acting serpins (Wang et al, 2008). PAR2 therefore plays a part in regulation of microglia activity.…”

Discoveries of Serine Protease Inhibitors from Scorpions

“…These proteins inhibit activity of proteases by a conserved pathway using a profound conformational change [1][2][3]. Among all PIs, serine protease inhibitors are the largest and most widely distributed superfamily of PIs [4][5][6].…”

“…Serine proteases, serine protease inhibitors, and protease-activated receptors have been intensively investigated in the periphery and their roles in a wide range of processes, such as coagulation, inflammation, and digestion [3,4,[28][29][30]. Protease inhibitors, trypsin inhibitors, such as ulinastatin and aprotinin, are already being clinically used in antiinflammatory therapy [31].…”