title: Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block.
abstract: 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 muM 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.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Shavit
authors.forename: Orit
authors.initials: O
authors.lastname: Beilin
authors.forename: Amos D
authors.initials: AD
authors.lastname: Korczyn
authors.forename: Constantin
authors.initials: C
authors.lastname: Sylantiev
authors.forename: Ramona
authors.initials: R
authors.lastname: Aronovich
authors.forename: Vivian E
authors.initials: VE
authors.lastname: Drory
authors.forename: David
authors.initials: D
authors.lastname: Gurwitz
authors.forename: Ido
authors.initials: I
authors.lastname: Horresh
authors.forename: Rachel
authors.initials: R
authors.lastname: Bar-Shavit
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism*; D009412:Nerve Fibers / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D011901:Ranvier's Nodes / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012584:Sciatic Nerve / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D044463:Receptor, PAR-1; D048049:Extracellular Signal-Regulated MAP Kinases; D013917:Thrombin