CGRP stimulation of iNOS and NO release from trigeminal ganglion glial cells involves mitogen-activated protein kinase pathways.
Clinical and basic science data support an integral role of calcitonin gene-related peptide (CGRP) in the pathophysiology of temporomandibular joint disorders. Recently, we have shown that CGRP can stimulate the synthesis and release of nitric oxide (NO) from trigeminal ganglion glial cells. The goal of this study was to determine the role of mitogen-activated protein kinase (MAPK) signaling pathways in CGRP regulation of iNOS expression and NO release from cultured trigeminal ganglion glial cells from Sprague-Dawley rats. CGRP treatment for 2 h significantly increased activity of the MAPK reporter genes, Elk, ATF-2, and CHOP. In addition, CGRP increased nuclear staining for the active forms of the MAPKs: extracellular signal-regulated kinase, c-Jun amino-terminal kinase, and p38. This stimulatory event was not observed in cultures pre-treated with the CGRP receptor antagonist peptide CGRP(8-37). Similarly, pre-treatment with selective MAPK inhibitors repressed increases in reporter gene activity as well as CGRP-induced increases in iNOS expression and NO release mediated by MAPKs. In addition, over-expression of MAPK kinase 1 (MEK1), MEK3, MEK6, and MEK kinase significantly increased iNOS expression and NO production in glial cells. Results from our study provide evidence that CGRP binding to its receptor can stimulate iNOS gene expression via activation of MAPK pathways in trigeminal ganglion glial cells.
Vause
C V
CV
Department of Biology, Missouri State University, Springfield, Missouri 65897, USA.
Durham
P L
PL
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D018015:Receptors, Calcitonin Gene-Related Peptide; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D015740:Calcitonin Gene-Related Peptide