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Protease‐activated receptors (PARs), microglial reactivity and neurodegeneration
Author(s) -
Suo Z.,
Citron B. A.,
Ameenuddin S.,
AndradeGordon P.,
Festoff B. W.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.81.s1.113.x
Subject(s) - neurodegeneration , microglia , thrombin , p38 mitogen activated protein kinases , microbiology and biotechnology , neuroglia , receptor , kinase , tumor necrosis factor alpha , mapk/erk pathway , biology , neuroscience , chemistry , endocrinology , medicine , immunology , inflammation , central nervous system , biochemistry , platelet , disease
Microglial activity accompanies many types of neurodegeneration and neurotrauma. Thrombin is an early arriving modulator at sites of CNS damage. How it affects cascades leading to neurodegeneration is an area of important study. To investigate the roles of PARs in thrombin‐induced microglial activation, primary microglial cultures from wild type and PAR1 deficient (PAR1 −/−) mice, along with N9 microglial cell line, were treated with thrombin, PAR1 (SFLLRN) and PAR4 (GYPGQV) agonist peptides (AP). Changes in [Ca 2+ ] i , phosphorylation states of mitogen‐activated protein kinases (MAPKs), p38, p44/42, cell proliferation and tumor necrosis factor‐α (TNFα) secretion were examined by calcium imaging, Western blots, MTS assay and ELISA. We found that activation of microglial PAR1 or PAR4 induces a rapid cytosolic free [Ca 2+ ] i increase and transient activation of both p38 and p44/42 MAPKs. Moreover, activation of either PAR1 or PAR4 directly contributes to thrombin‐induced microglial proliferation. In addition, activation of PAR4, but not PAR1, alone mimics the direct effect of thrombin on TNF‐α induction. Nonetheless, activation of PAR1 by PAR1AP potentiates PAR4AP‐induced TNF‐α production. We conclude that activation of PAR1 and PAR4 alone each contributes to different aspects of microglial activation by thrombin. In addition, PAR1 and PAR4 function in concert to mediate thrombin's overall effect on microglia. Acknowledgements: Supported by V.A. Medical Research, Missouri Alzheimer's Research Fund, Univ. of Kansas medical Center Research Institute, ALS Association, Chrsitorpher reeve Paralysis Foundation, Lied Endowment and Midwest Biomedical Research Foundation.