Activation of extracellular signal‐regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain

Lindgren, Niklas; Goiny, Michel; Herrera‐Marschitz, Mario; Haycock, John W.; Hökfelt, Tomas; Fisone, Gilberto

doi:10.1046/j.1460-9568.2002.01901.x

Cited by 87 publications

(87 citation statements)

References 22 publications

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“…This raises the interesting possibility that phosphorylation of Ser-31 may actually facilitate the interaction between Ser-19 and Ser-40. This notion is consistent with recent work (19) that suggests that inhibiting MAP kinase-induced phosphorylation of Ser-31 also leads to an increase in Ser-40 phosphorylation.…”

Section: Figsupporting

confidence: 93%

“…However, only phosphorylation of Ser-19, Ser-31, and Ser-40 has been associated with an increase in enzyme activity (14,15 (13,14). The phosphorylation of Ser-31 is unique in that it is accomplished by the mitogenactivated protein (MAP) 1 kinases, ERK1 and ERK2 (13,18,19). Although MAP kinase-mediated phosphorylation of Ser-31 is associated with a modest 2-fold increase in enzyme activity, phosphorylation at this site appears to be a physiologically important mechanism for the stimulation of catecholamine production in a variety of different tissues (18,19,20).…”

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confidence: 99%

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Phosphorylation-induced Conformational Changes in a Mitogen-activated Protein Kinase Substrate

Stultz

Levin

Edelman

2002

Journal of Biological Chemistry

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Mitogen-activated protein (MAP) kinase-mediated phosphorylation of specific residues in tyrosine hydroxylase leads to an increase in enzyme activity. However, the mechanism whereby phosphorylation affects enzyme turnover is not well understood. We used a combination of fluorescence resonance energy transfer (FRET) measurements and molecular dynamics simulations to explore the conformational free energy landscape of a 10-residue MAP kinase substrate found near the N terminus of the enzyme. This region is believed to be part of an autoregulatory sequence that overlies the active site of the enzyme. FRET was used to measure the effect of phosphorylation on the ensemble of peptide conformations, and molecular dynamics simulations generated free energy profiles for both the unphosphorylated and phosphorylated peptides. We demonstrate how FRET transfer efficiencies can be calculated from molecular dynamics simulations. For both the unphosphorylated and phosphorylated peptides, the calculated FRET efficiencies are in excellent agreement with the experimentally determined values. Moreover, the FRET measurements and molecular simulations suggest that phosphorylation causes the peptide backbone to change direction and fold into a compact structure relative to the unphosphorylated state. These results are consistent with a model of enzyme activation where phosphorylation of the MAP kinase substrate causes the N-terminal region to adopt a compact structure away from the active site. The methods we employ provide a general framework for analyzing the accessible conformational states of peptides and small molecules. Therefore, they are expected to be applicable to a variety of different systems.Phosphorylation of specific amino acids near the surface of a protein is an almost universal mechanism of protein activation that has been long appreciated (1,2). Yet the mechanism whereby phosphorylation modifies the activity of the protein is not well understood (1). Analysis of phosphorylation sites from different enzymes reveals common themes. In eukaryotes, phosphorylation typically occurs at tyrosine, threonine, or serine side chains, and these phosphorylated residues often form a network of hydrogen bonds with adjacent positively charged arginine residues (1,(3)(4)(5)(6). The network of hydrogen bonds and salt bridges that form can then communicate phosphorylation to distant areas of the protein (6). In the case of yeast glycogen phosphorylase, phosphorylation occurs at a threonine residue located near the N terminus, a region that overlies the active site of the enzyme (3). The enzyme, which normally exists as a homodimer, contains two active catalytic sites, one in each monomer (3). Phosphorylation at this site causes the N-terminal region to fold into a compact structure that wedges between the dimer interface. This structural change helps to reorient the active site in a manner that facilitates enzymatic activation (3). Examples such as this suggest that large scale movements of flexible regions within a protein are an impor...

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Section: Figsupporting

confidence: 93%

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confidence: 99%

Phosphorylation-induced Conformational Changes in a Mitogen-activated Protein Kinase Substrate

Stultz

Levin

Edelman

2002

Journal of Biological Chemistry

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“…It is therefore possible that the decrease in TH phosphorylation produced by quinpirole is mediated via Gi-dependent inhibition of adenylyl cyclase, reduction of cAMP levels, and inhibition of PKA activity. However, other studies have implicated extracellular signal-regulated kinases 1 and 2 (ERK1͞2) in the increase in Ser-40 phosphorylation produced by depolarization (38). In addition, recent evidence demonstrated the existence of a negative regulation exerted by D2 receptors on striatal ERK1͞2 (39).…”

Section: Resultsmentioning

confidence: 99%

Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites

Lindgren

Usiello

Goiny

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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172

144

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Dopamine D2 receptors are highly expressed in the dorsal striatum where they participate in the regulation of (i) tyrosine hydroxylase (TH), in nigrostriatal nerve terminals, and (ii) the dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), in medium spiny neurons. Two isoforms of the D2 receptor are generated by differential splicing of the same gene and are referred to as short (D2S) and long (D2L) dopamine receptors. Here we have used wild-type mice, dopamine D2 receptor knockout mice (D2 KO mice; lacking both D2S and D2L receptors) and D2L receptor-selective knockout mice (D2L KO mice) to evaluate the involvement of each isoform in the regulation of the phosphorylation of TH and DARPP-32. Incubation of striatal slices from wild-type mice with quinpirole, a dopamine D2 receptor agonist, decreased the state of phosphorylation of TH at Ser-40 and its enzymatic activity. Both effects were abolished in D2 KO mice but were still present in D2L KO mice. In wild-type mice, quinpirole inhibits the increase in DARPP-32 phosphorylation at Thr-34 induced by SKF81297, a dopamine D1 receptor agonist. This effect is absent in D2 KO as well as D2L KO mice. The inability of quinpirole to regulate DARPP-32 phosphorylation in D2L KO mice cannot be attributed to decreased coupling of D2S receptors to G proteins, because quinpirole produces a similar stimulation of [ 35 S]GTP␥S binding in wild-type and D2L KO mice. These results demonstrate that D2S and D2L receptors participate in presynaptic and postsynaptic dopaminergic transmission, respectively. D opamine acts by binding to five subtypes of heptahelical G protein-coupled receptors (1-3), which have been divided into two groups: the D1-like receptors, comprising D1 and D5 receptors, both positively coupled to adenylyl cyclase and cAMP production, and the D2-like receptors, comprising D2, D3, and D4 receptors, whose activation results in inhibition of adenylyl cyclase and suppression of cAMP production (4, 5). The D2 subtype of dopamine receptor represents the main autoreceptor of the dopaminergic system (6-11), but is also critical for postsynaptic transmission (3,10,12). This receptor has been the subject of extensive studies, which have demonstrated its participation in numerous important physiological functions, such as synthesis and release of pituitary hormones (13-15) and control of motor activity (12,16,17). Dopamine D2 receptors represent the major target of antipsychotic drugs and are involved in various neuropathological conditions, including Parkinson's disease, Tourette's syndrome, and drug addiction (3,12,18,19).Alternative mRNA splicing generates two isoforms of the dopamine D2 receptor, named long (D2L) and short (D2S) isoforms (20), which differ by an insertion of 29 aa in the third intracellular loop of the D2L receptor. Both isoforms function by binding to pertussis toxin-sensitive G proteins, which reduce adenylyl cyclase activity. However, previous studies have shown that D2L and D2S receptors bind to distinct Gi proteins, most likely as a res...

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“…In addition, repeated cocaine exposure increases tyrosine hydroxylase (TH-the rate-limiting enzyme in dopamine synthesis) enzyme activity in the ventral tegmental area along with basal ERK catalytic activity (Vrana et al, 1993;Berhow et al, 1996). Given that blockade of the Raf-MEK-ERK signaling cascade decreases depolarization-induced phosphorylation of TH and subsequent accumulation of the dopamine precursor DOPA in striatal slices (Lindgren et al, 2002), these data suggest that ERK signaling may also regulate the neurochemical changes (eg augmented dopamine neurotransmission) associated with cocaine treatment. Nonetheless, given the complex interactions between the various signaling cascades, it is worth noting that there could be, as yet unidentified, compensatory changes in other signaling cascades that could contribute to the results seen in the present experiments.…”

Section: Discussionmentioning

confidence: 99%

Knockout of ERK1 Enhances Cocaine-Evoked Immediate Early Gene Expression and Behavioral Plasticity

Ferguson

Fasano

Yang

et al. 2006

Neuropsychopharmacol

110

100

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The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.

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Activation of extracellular signal‐regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain

Cited by 87 publications

References 22 publications

Phosphorylation-induced Conformational Changes in a Mitogen-activated Protein Kinase Substrate

Phosphorylation-induced Conformational Changes in a Mitogen-activated Protein Kinase Substrate

Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites

Knockout of ERK1 Enhances Cocaine-Evoked Immediate Early Gene Expression and Behavioral Plasticity

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