Regulation of functional nitric oxide synthase-1 expression in cerebellar granule neurons by heregulin is post-transcriptional, and involves mitogen-activated protein kinase.
The neuregulins, and the ErbB family of tyrosine kinase receptors, play important roles in the development of the nervous system. Recently, the C-terminal region of the ErbB4 receptor has been reported to associate with domains of post-synaptic density proteins. The latter are, in turn, known to assemble nitric oxide synthase (NOS)-1 at cell junctions. Previously, we showed that heregulin can up-regulate the expression of NOS-1 via the ErbB4 receptor in cerebellar granule cell cultures. We have now determined that this up-regulation is post-transcriptional, and results in an associated increase in NOS activity in these neurons. Furthermore, we find that heregulin activates both MAP kinase and phosphoinositide 3 kinase (PI 3-K) in granule cells. While inhibition of MAP kinase reduces the ability of heregulin to up-regulate NOS-1 expression, a specific inhibitor of PI 3-K was without effect. Our results suggest that NO could mediate some of the downstream effects of heregulin in the nervous system.
Krainock
R
R
Department of Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa, USA.
Murphy
S
S
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002458:Cell Fractionation; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020890:Neuregulin-1 / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D066247:Receptor, ErbB-4; D015854:Up-Regulation; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D019833:Genistein; D020928:Mitogen-Activated Protein Kinases; D019331:NG-Nitroarginine Methyl Ester; D020890:Neuregulin-1; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D066247:Receptor, ErbB-4; D000077191:Wortmannin; C496321:Nos1 protein, mouse; C587690:Erbb4 protein, mouse