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

Abstract

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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