Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons.
Calcitonin gene-related peptide (CGRP) and nitric oxide are involved in the underlying pathophysiology of migraine and other diseases involving neurogenic inflammation. We have tested the hypothesis that nitric oxide might trigger signaling mechanisms within the trigeminal ganglia neurons that would coordinately stimulate CGRP synthesis and release. Treatment of primary trigeminal ganglia cultures with nitric oxide donors caused a greater than four-fold increase in CGRP release compared with unstimulated cultures. Similarly, CGRP promoter activity was also stimulated by nitric oxide donors and overexpression of inducible nitric oxide synthase (iNOS). Cotreatment with the antimigraine drug sumatriptan greatly repressed nitric oxide stimulation of CGRP promoter activity and secretion. Somewhat surprisingly, the mechanisms of nitric oxide stimulation of CGRP secretion did not require cGMP or PI3-kinase signaling pathways, but rather, nitric oxide action required extracellular calcium and likely involves T-type calcium channels. Furthermore, nitric oxide was shown to increase expression of the active forms of the mitogen-activated protein kinases Jun amino-terminal kinase and p38 but not extracellular signal-related kinase in trigeminal neurons. In summary, our results provide new insight into the cellular mechanisms by which nitric oxide induces CGRP synthesis and secretion from trigeminal neurons.
Bellamy
Jamie
J
Department of Biology, 225 Temple Hall, Missouri State University, Springfield, MO 65897, USA.
Bowen
Elizabeth J
EJ
Russo
Andrew F
AF
Durham
Paul L
PL
D000818:Animals; D000831:Animals, Newborn; D019256:Cadmium Chloride / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D011985:Receptors, Serotonin; C110881:S-nitro-N-acetylpenicillamine; D017366:Serotonin Receptor Agonists; D009569:Nitric Oxide; D011189:Potassium Chloride; D018170:Sumatriptan; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D010396:Penicillamine; D019256:Cadmium Chloride; D015740:Calcitonin Gene-Related Peptide