title: Sustained phosphorylation of tyrosine hydroxylase at serine 40: a novel mechanism for maintenance of catecholamine synthesis.
abstract: Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine synthesis. Its activity is known to be controlled acutely (minutes) by phosphorylation and chronically (days) by protein synthesis. Using bovine adrenal chromaffin cells we found that nicotine, acting via nicotinic receptors, sustained the phosphorylation of TH at Ser40 for up to 48 h. Nicotine also induced sustained activation of TH, which for the first 24 h was completely independent of TH protein synthesis, and the phosphorylation of TH at Ser31. Imipramine did not inhibit the acute phosphorylation of TH at Ser40 or TH activation induced by nicotine, but did inhibit the sustained responses to nicotine seen at 24 h. The protein kinase(s) responsible for TH phosphorylation at Ser40 switched from being protein kinase C (PKC) independent in the acute phase to PKC dependent in the sustained phase. Sustained phosphorylation and activation of TH were also observed with histamine and angiotensin II. Sustained phosphorylation of TH at Ser40 provides a novel mechanism for increasing TH activity and this leads to increased catecholamine synthesis. Sustained phosphorylation of TH may be a selective target for drugs or pathology in neurons that contain TH and synthesize dopamine, noradrenaline or adrenaline.
authors.affiliation: School of Biomedical Sciences and Hunter Medical Research Institute, Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Larisa
authors.initials: L
authors.lastname: Bobrovskaya
authors.forename: Conor
authors.initials: C
authors.lastname: Gilligan
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Bolster
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Flaherty
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Dickson
authors.forename: Peter R
authors.initials: PR
authors.lastname: Dunkley
mesh_terms: D000311:Adrenal Glands / Q000166:cytology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology; D007211:Indoles; D008301:Maleimides; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D012694:Serine / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry / Q000378:metabolism*
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D018759:Adrenergic Uptake Inhibitors; D002227:Carbazoles; D002395:Catecholamines; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D018722:Nicotinic Agonists; D011500:Protein Synthesis Inhibitors; D000804:Angiotensin II; D012694:Serine; D009538:Nicotine; D003513:Cycloheximide; D014446:Tyrosine 3-Monooxygenase; D048049:Extracellular Signal-Regulated MAP Kinases; D007099:Imipramine