title: Activation of extracellular signal-regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain.
abstract: Production of dopamine is regulated via phosphorylation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines. Here we have used a preparation of rat striatal slices to examine the involvement of two mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), in the depolarization-dependent regulation of TH phosphorylation and dopamine synthesis. Depolarization with elevated KCl (45 mm) caused an increase in the phosphorylation state and, thereby, activation of ERK1/2. The same stimulus also increased TH phosphorylation at Ser19, Ser31 and Ser40 (measured using site- and phospho-specific antibodies) and TH activity [measured as 3,4-dihydroxyphenylalanine (DOPA) accumulation]. A MAPK/ERK kinase inhibitor, PD098059, decreased the basal levels of phospho-ERK1/2 and prevented the increase in ERK1/2 phosphorylation induced by depolarization. PD098059 also decreased both basal and depolarization-induced phosphorylation of TH at Ser31 and reduced the increase in Ser40 phosphorylation induced by high potassium, but did not affect Ser19 phosphorylation. PD098059 alone inhibited basal TH activity and decreased the accumulation of DOPA induced by depolarization. These data provide evidence for the involvement of ERK1/2 in the regulation of the state of phosphorylation of TH at Ser31 and Ser40 and a correlation between ERK1/2-dependent phosphorylation of TH and stimulation of dopamine synthesis in the brain.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindgren
authors.forename: Michel
authors.initials: M
authors.lastname: Goiny
authors.forename: Mario
authors.initials: M
authors.lastname: Herrera-Marschitz
authors.forename: John W
authors.initials: JW
authors.lastname: Haycock
authors.forename: Tomas
authors.initials: T
authors.lastname: Hökfelt
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D004298:Dopamine / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D005576:Colforsin; D012694:Serine; D011189:Potassium Chloride; 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; D004298:Dopamine