Journal Article

Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block

Efrat Shavit, Orit Beilin, Amos D. Korczyn, Constantin Sylantiev, Ramona Aronovich, Vivian E. Drory, David Gurwitz, Ido Horresh, Rachel Bar-Shavit, Elior Peles and Joab Chapman

in Brain

Published on behalf of The Guarantors of Brain

Volume 131, issue 4, pages 1113-1122
Published in print April 2008 | ISSN: 0006-8950
Published online February 2008 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awn005
Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block

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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.

Keywords: protease activated receptors; thrombin; node of Ranvier; conduction block

Journal Article.  6175 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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