Regulation and physiological role of tyrosine hydroxylase phosphorylation in the striatum
Author: Lindgren, Niklas
Date: 2003-02-28
Location: Hillarpsalen, Retziuslaboratoriet, Retzius väg 8, Stockholm
Time: 9.00
Department: Institutionen för neurovetenskap / Department of Neuroscience
Abstract
Tyrosine hydroxylase (TH) catalyses the conversion of tyrosine to DOPA and is the rate- limiting enzyme in the biosynthesis of catecholamines, a group of neurotransmitters involved in various brain functions. Short-term regulation of TH activity is achieved by phosphorylation of the protein's regulatory domain at three seryl residues in positions 19, 31 and 40.
This thesis focuses on the investigation of the molecular mechanisms involved in the regulation of the state of phosphorylation and activity of TH in the striatum, a region of the brain implicated in motor control and associative learning. Dopamine is the most abundant catecholamine in the brain and plays a critical role in striatal function, as dramatically shown by the severe motor impairment caused by degeneration of cloparninergic nigrostriatal neurons, occurring in Parkinson's disease. In slices of rat striatum, activation of glutamate NMDA receptors inhibits dopamine synthesis by reducing cAMP levels and decreasing cAMP-dependent protein kinase catalysed phosphorylation of TH at Ser4O. Synthesis of striatal dopamine is controlled by dopamine D2 autoreceptors located on nigrostriatal nerve terminals.
It is demonstrated that such a control specifically involves the short isoform (D2S) of the dopamine D2 receptor. In addition, evidence is provided indicating that activation of D2S receptors reduces TH activity via inhibition of cAMP production and decrease in TH phosphorylation at Ser40. This effect is likely to result in reduced dopamine synthesis, which may ultimately affect neurotransmitter release.
Finally, it is shown that high K+- induced depolarization increases TH activity via stimulation of extracellular signal- activated protein kinases I and 2 (ERK1/2), two mitogen -activated protein kinases (MAPKs). This effect is accompanied by E RK 1/2-depen dent phosphorylation of TH at Ser31 and Ser4O, but not at Ser19. These results demonstrate that, in the brain, the MAPK cascade is involved in short-term regulation of presynaptic cloparninergic transmission.
This thesis focuses on the investigation of the molecular mechanisms involved in the regulation of the state of phosphorylation and activity of TH in the striatum, a region of the brain implicated in motor control and associative learning. Dopamine is the most abundant catecholamine in the brain and plays a critical role in striatal function, as dramatically shown by the severe motor impairment caused by degeneration of cloparninergic nigrostriatal neurons, occurring in Parkinson's disease. In slices of rat striatum, activation of glutamate NMDA receptors inhibits dopamine synthesis by reducing cAMP levels and decreasing cAMP-dependent protein kinase catalysed phosphorylation of TH at Ser4O. Synthesis of striatal dopamine is controlled by dopamine D2 autoreceptors located on nigrostriatal nerve terminals.
It is demonstrated that such a control specifically involves the short isoform (D2S) of the dopamine D2 receptor. In addition, evidence is provided indicating that activation of D2S receptors reduces TH activity via inhibition of cAMP production and decrease in TH phosphorylation at Ser40. This effect is likely to result in reduced dopamine synthesis, which may ultimately affect neurotransmitter release.
Finally, it is shown that high K+- induced depolarization increases TH activity via stimulation of extracellular signal- activated protein kinases I and 2 (ERK1/2), two mitogen -activated protein kinases (MAPKs). This effect is accompanied by E RK 1/2-depen dent phosphorylation of TH at Ser31 and Ser4O, but not at Ser19. These results demonstrate that, in the brain, the MAPK cascade is involved in short-term regulation of presynaptic cloparninergic transmission.
List of papers:
I. Lindgren N, Xu ZQ, Lindskog M, Herrera-Marschitz M, Goiny M, Haycock J, Goldstein M, Hokfelt T, Fisone G (2000). Regulation of tyrosine hydroxylase activity and phosphorylation at Ser(19) and Ser(40) via activation of glutamate NMDA receptors in rat striatum. J Neurochem. 74(6): 2470-7.
Pubmed
II. Lindgren N, Xu ZQ, Herrera-Marschitz M, Haycock J, Hokfelt T, Fisone G (2001). Dopamine D(2) receptors regulate tyrosine hydroxylase activity and phosphorylation at Ser40 in rat striatum. Eur J Neurosci. 13(4): 773-80.
Pubmed
III. Lindgren N, Usiello A, Goiny M, Haycock J, Erbs E, Greengard P, Hokfelt T, Borreli E, Fisone G (2003). Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc Natl Acad Sci U S A. [Accepted]
IV. Lindgren N, Goiny M, Herrera-Marschitz M, Haycock JW, Hokfelt T, Fisone G (2002). Activation of extracellular signal-regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain. Eur J Neurosci. 15(4): 769-73.
Pubmed
I. Lindgren N, Xu ZQ, Lindskog M, Herrera-Marschitz M, Goiny M, Haycock J, Goldstein M, Hokfelt T, Fisone G (2000). Regulation of tyrosine hydroxylase activity and phosphorylation at Ser(19) and Ser(40) via activation of glutamate NMDA receptors in rat striatum. J Neurochem. 74(6): 2470-7.
Pubmed
II. Lindgren N, Xu ZQ, Herrera-Marschitz M, Haycock J, Hokfelt T, Fisone G (2001). Dopamine D(2) receptors regulate tyrosine hydroxylase activity and phosphorylation at Ser40 in rat striatum. Eur J Neurosci. 13(4): 773-80.
Pubmed
III. Lindgren N, Usiello A, Goiny M, Haycock J, Erbs E, Greengard P, Hokfelt T, Borreli E, Fisone G (2003). Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc Natl Acad Sci U S A. [Accepted]
IV. Lindgren N, Goiny M, Herrera-Marschitz M, Haycock JW, Hokfelt T, Fisone G (2002). Activation of extracellular signal-regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain. Eur J Neurosci. 15(4): 769-73.
Pubmed
Issue date: 2003-02-07
Publication year: 2003
ISBN: 91-7349-463-1
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