Regulation of human D1 dopamine receptor function and gene expression in SK-N-MC neuroblastoma cells

Sidhu, Anita; Olde, Björn; Humblot, Nathalie; Kimura, Kazuhiro; Gardner, Nina M.

doi:10.1016/s0306-4522(98)00555-7

Cited by 22 publications

(11 citation statements)

References 17 publications

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“…Chronic stimulation of D1 sites has been shown by us (31,38) and others (39 -42) to lead to the functional desensitization of the receptor with rapid loss of functional activity. The studies presented here show that there may be additional consequences of chronic increases in extracellular dopamine levels, which can cause profound cytotoxicity.…”

Section: Discussionmentioning

confidence: 93%

Chronic Stimulation of D1 Dopamine Receptors in Human SK-N-MC Neuroblastoma Cells Induces Nitric-oxide Synthase Activation and Cytotoxicity

Chen

Wersinger

Sidhu

2003

Journal of Biological Chemistry

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Elevated synaptic levels of dopamine may induce striatal neurodegeneration in L-DOPA-unresponsive parkinsonism subtype of multiple system atrophy (MSA-P subtype), multiple system atrophy, and methamphetamine addiction. We examined the participation of dopamine and D1 dopamine receptors in the genesis of postsynaptic neurodegeneration. Chronic treatment of human SK-N-MC neuroblastoma cells with dopamine or H 2 O 2 increased NO production and accelerated cytotoxicity, as indexed by enhanced nitrite levels and cell death. The antioxidant sodium metabisulfite or SCH 23390, a D1 dopamine receptor-selective antagonist, partially blocked dopamine effects but together ablated dopamine-mediated cytotoxicity, indicating the participation of both autoxidation and D1 receptor stimulation. Direct activation of D1 dopamine receptors with SKF R-38393 caused cytotoxicity, which was refractory to sodium metabisulfite. Dopamine and SKF R-38393 induced overexpression of the nitric-oxide synthase (NOS) isoforms neuronal NOS, inducible NOS (iNOS), and endothelial NOS in a protein kinase A-dependent manner. Functional studies showed that ϳ60% of total NOS activity was due to activation of iNOS. The NOS inhibitor N(G)-nitro-L-arginine methyl ester and genistein, wortmannin, or NF-B SN50, inhibitors of protein tyrosine kinases phosphatidylinositol 3-kinase and NF-B, respectively, reduced nitrite production by dopamine and SKF R-38393 but were less effective in attenuating H 2 O 2 -mediated effects. In rat striatal neurons, dopamine and SKF R-38393, but not H 2 O 2 , accelerated cell death through increased expression of neuronal NOS and iNOS but not endothelial NOS. These data demonstrate a novel pathway of dopamine-mediated postsynaptic oxidative stress and cell death through direct activation of NOS enzymes by D1 dopamine receptors and its associated signaling pathways.Striatonigral neurodegeneration is implicated in the clinical expression of several human disorders and addictive states involving dopamine neuronal dysfunction, such as MSA, 1 L-DOPA-unresponsive parkinsonism subtype of multiple system atrophy (MSA-P subtype) (1), secondary dopamine dysfunction in Huntington's disease (HD), and methamphetamine (METH)-induced neurotoxicity (2, 3), in which dopaminergic transmission is interrupted by progressive loss of striatal neurons bearing postsynaptic D1 and D2 dopamine receptors (4). Moreover, striatonigral neurodegeneration was also observed in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 3-nitropropionic acid (5). Recent studies implicate the participation of both reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the pathophysiology of striatonigral neurodegeneration (5-8) through mechanisms that remain undefined.Because striatal neurons do not produce dopamine or express the dopamine transporter (DAT), the mechanism of dopaminemediated neurotoxicity in such neurons occurs through extracellularly present dopamine in the synapse (9, 10). Normally, dopamine released into the synapse is r...

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Section: Discussionmentioning

confidence: 93%

Chronic Stimulation of D1 Dopamine Receptors in Human SK-N-MC Neuroblastoma Cells Induces Nitric-oxide Synthase Activation and Cytotoxicity

Chen

Wersinger

Sidhu

2003

Journal of Biological Chemistry

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“…receptor selective agonist, SKF R-38393, causes profound cytotoxicity, as indexed by increased oxidative stress and accelerated cell death (14). SK-N-MC neuroblastoma cells, a postsynaptic striatal cell model endogenously expressing the D1 receptors (15,27), were treated with increasing concentrations of dopamine in the presence of SCH 23390, a D1-selective antagonist, or SMBS, a potent antioxidant. In the presence of either of these two compounds, the cytotoxic effects of dopamine were reduced sharply by ϳ50%, as indexed by a decrease in both nitrite production (Fig.…”

Section: Methodsmentioning

confidence: 99%

D1 Dopamine Receptor Mediates Dopamine-induced Cytotoxicity via the ERK Signal Cascade

Chen

Rusnak

Luedtke

et al. 2004

Journal of Biological Chemistry

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Postsynaptic striatal neurodegeneration occurs through unknown mechanisms, but it is linked to high extracellular levels of synaptic dopamine. Dopaminemediated cytotoxicity of striatal neurons occurs through two distinct pathways: autoxidation and the D1 dopamine receptor-linked signaling pathway. Here we investigated the mitogen-activated protein kinase (MAPK) signaling pathways activated upon the acute stimulation of D1 dopamine receptors. In SK-N-MC neuroblastoma cells, endogenously expressing D1 dopamine receptors, dopamine caused activation of phosphorylated (p-)ERK1/2 and of the stress-signaling kinases, p-JNK and p-p38 MAPK, in a time-and dose-dependent manner. Selective stimulation of D1 receptors with the agonist SKF R-38393 caused p-ERK1/2, but not p-JNK or p-p38 MAPK activation, in a manner sensitive to the receptor-selective antagonist SCH 23390, protein kinase A inhibition (KT5720), and MEK1/2 inhibition (U0126 or PD98059). Activation of ERK by D1 dopamine receptors resulted in oxidative stress and cytotoxicity. In cells transfected with a catalytically defective mutant of MEK1, the upstream ERK-specific kinase, both dopamine-and SKF R-38393-mediated cytotoxicity was markedly attenuated, confirming the participation of the ERK signaling pathway. Cell fractionation studies showed that only a small amount of p-ERK1/2 was translocated to the nucleus, with the majority retained in the cytoplasm. From coimmunoprecipitation studies, p-ERK was found to form stable heterotrimeric complexes with the D1 dopamine receptor and ␤-arrestin2. In cells transfected with the dominant negative mutant of ␤-arrestin2, the formation of such complexes was substantially inhibited. These data provide novel mechanistic insights into the role of ERK in the cytotoxicity mediated upon activation of the D1 dopamine receptor.Striatal neurodegeneration is found in several human disorders involving postsynaptic dopamine neuronal dysfunction, such as the L-dopa-unresponsive parkinsonism subtype of multiple system atrophy (1), methamphetamine-induced neurotoxicity (2, 3), and secondary dopamine dysfunction in Huntington's disease (4), in which dopaminergic transmission is interrupted by progressive loss of the striatal neurons bearing the postsynaptic D1 and D2 dopamine receptors (5). Although all of these diseases are characterized by elevated dopamine levels in the synapse, the underlying pathological mechanism(s) promoting striatal degeneration remains enigmatic. Recent studies suggest a role for the participation of both reactive oxygen species and reactive nitrogen species in the degeneration of striatal neurons (6 -9). Reactive oxygen species and reactive nitrogen species may be produced through autoxidation of extracellular dopamine in the synapse and may be especially important in the striatal degeneration seen in the L-dopa-unresponsive parkinsonism subtype of multiple system atrophy (1, 10).Dopamine in the synapse causes activation of the postsynaptic D1 and D2 subtypes of the dopamine receptor. Accumulating evidence in pri...

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“…3a) could be related to minimal DA release in mild hypoxia versus higher DA release in severe hypoxia. A bimodal feedback regulatory pattern has been observed for DA D 1 -R mRNA level in neuroblastoma cells [23], where low concentrations of DA up-regulate while higher concentrations down-regulate D 1 -R mRNA level. Another mechanism could be related to an interaction between normal maturational changes in D 2 -and D 1 -R mRNA levels and the increase in mRNA stability in response to hypoxia [24,25].…”

Section: Possible Mechanismsmentioning

confidence: 95%

Differential Changes in Dopamine D<sub>2</sub>- and D<sub>1</sub>-Receptor mRNA Levels Induced by Hypoxia in the Arterial Chemoreflex Pathway Organs in One-Day-Old and Adult Rabbits

Bairam

Carroll²,

Labelle³

et al. 2003

Neonatology

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This study determined: (1) whether dopamine (DA) D₂-receptor (R) and D₁-R mRNA levels in the carotid body (CB), petrosal ganglion (PG) and superior cervical ganglion (SCG) are modulated by hypoxia; (2) the role of hypoxia intensity and exposure duration, and (3) whether the pattern of modulation differs between newborn (1-day-old) and adult rabbits. Rabbits were exposed to five F_iO₂ conditions: 21% (control); 15%/6 h; 15%/24 h; 8%/6 h and 8%/24 h. D₂- and D₁-R mRNA expression levels were calculated for each hypoxia condition relative to control using RT-PCR analysis. In the CB of 1-day-old rabbits, D₂- and D₁-R transcript levels increased and decreased after exposure to 15 and 8% O₂, respectively. In the adult CB, D₂- and D₁-R transcript levels decreased independently of hypoxia intensities. Only changes in D₁-R mRNA levels were dependent on exposure time. In the PG, both hypoxia intensities decreased the D₂-R transcript levels in 1-day-old and adult rabbits; but for the D₁-R mRNA levels, hypoxia decreased its level in 1-day-old rabbits and increased it in adults regardless of exposure duration. In the SCG, hypoxia had no determinant effect on the D₂-R mRNA levels either in newborn or adult rabbits while it induced a decrease of D₁-R transcript levels in 1-day-old rabbits and an increase in adult rabbits. It is concluded that hypoxia affects DA D₂- or D₁-R mRNA levels in the chemoreflex pathway in an age-dependent and site-specific manner.

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Regulation of human D1 dopamine receptor function and gene expression in SK-N-MC neuroblastoma cells

Cited by 22 publications

References 17 publications

Chronic Stimulation of D1 Dopamine Receptors in Human SK-N-MC Neuroblastoma Cells Induces Nitric-oxide Synthase Activation and Cytotoxicity

Chronic Stimulation of D1 Dopamine Receptors in Human SK-N-MC Neuroblastoma Cells Induces Nitric-oxide Synthase Activation and Cytotoxicity

D1 Dopamine Receptor Mediates Dopamine-induced Cytotoxicity via the ERK Signal Cascade

Differential Changes in Dopamine D<sub>2</sub>- and D<sub>1</sub>-Receptor mRNA Levels Induced by Hypoxia in the Arterial Chemoreflex Pathway Organs in One-Day-Old and Adult Rabbits

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