Brain Advance Access originally published online on February 25, 2008
Brain 2008 131(4):1113-1122; doi:10.1093/brain/awn005
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Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block
1Department of Physiology and Pharmacology, 2Department of Neurology, 3Sieratzki Chair of Neurology, 4Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, 5Department of Molecular Cell Biology, Weizmann Institute for Scientific Research, Rehovot and 6Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel
Correspondence to: Professor Joab Chapman, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel E-mail: jchapman{at}post.tau.ac.il
Inflammatory demyelinating diseases of peripheral nerves are associated with altered nerve conduction and with activation of the coagulation pathway. Thrombin mediates many of its effects through protease-activated receptor 1 (PAR-1). We examined the possibility that thrombin may mediate conduction abnormalities through PAR-1 on rat sciatic nerve. PAR-1 was found to be present by both RT-PCR and Western blot analysis of the sciatic nerve. Activation of PAR-1 by a specific peptide agonist caused a 3-fold increase in phosphorylated extracellular signal-regulated kinase (ERK) in the sciatic nerve indicating the existence of functional receptors in the nerve. By confocal immunofluoresence microscopy of the sciatic nerve using anti-PAR-1 antibody and double staining for the paranodal marker contactin-associated protein 1 (Caspr1) or the nodal markers gliomedin and ezrin, the receptor was localized predominantly to myelin microvilli at the node of Ranvier. Thrombin and the PAR-1-specific agonist were applied to exposed rat sciatic nerve and their effects on nerve conduction were measured. Thrombin at concentrations of 100 and 200 U/ml and PAR-1 agonists 150 and 300 µM produced a conduction block within 30 min of application. This effect was maintained for at least 1 h and was reversible by washing. The function of the nodal non-compacted myelin is not well known. The current results implicate this structure and PAR-1 activation in the pathogenesis of conduction block in inflammatory and thrombotic nerve diseases.
Key Words: protease activated receptors; thrombin; node of Ranvier; conduction block
Abbreviations: BBB, blood–brain barrier; BNB, blood–nerve barrier; CNS, central nervous system; DRG, dorsal root ganglia; EAN, experimental autoimmune neuritis; GBS, Guillain–Barre syndrome; PNS, peripheral nervous system
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Received April 26, 2007. Revised December 29, 2007. Accepted January 8, 2008.
*These authors contributed equally to this work.