Ca2+ -dependent activation of tyrosine hydroxylase involves MEK1.
Tyrosine hydroxylase (TOH) activity is regulated acutely by phosphorylation of serines 8, 19, 31 and 40. The only kinases known to phosphorylate Ser31 are the mitogen-activated protein kinases MAPK-1 and 2. The involvement of these kinases in TOH activation in situ was therefore investigated using intact bovine chromaffin cells. Nicotine, K+ and A23187 increased TOH activity over 10 min in a Ca2+-dependent manner. The response to all three was reduced by PD098059, a selective inhibitor of the upstream activator of MAPK, MEK1. In contrast, TOH activation by forskolin and phorbol dibutyrate were unaffected by PD098059. The results support a key role for MEK1/MAPK in the acute activation of TOH by nicotinic receptors and by other agonists that increase cytosolic Ca2+.
Griffiths
J
J
Department of Pharmacology, University of Melbourne, Victoria 3010, Australia.
Marley
P D
PD
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007476:Ionophores; D018722:Nicotinic Agonists; D009538:Nicotine; D014446:Tyrosine 3-Monooxygenase; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D011188:Potassium; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium