Abstract
Dopamine D2 receptor (D2R)-mediated extracellular signal-regulated kinase (ERK) activation plays an important role in the development of dopaminergic mesencephalic neurons. Here, we demonstrate that D2R induces the shedding of heparin-binding epidermal growth factor (EGF) through the activation of a disintegrin and metalloprotease (ADAM) 10 or 17, leading to EGF receptor transactivation, downstream ERK activation, and ultimately an increase in the number of dopaminergic neurons and their neurite length in primary mesencephalic cultures from wild-type mice. These outcomes, however, were not observed in cultures from D2R knock-out mice. Our findings show that D2R-mediated ERK activation regulates mesencephalic dopaminergic neuron development via EGF receptor transactivation through ADAM10/17.
Highlights
Dopamine D2 receptor (D2R)-mediated extracellular signalregulated kinase (ERK) activation regulates dopaminergic neuronal development
ERK activation has been found to occur in response to D2R stimulation in mesencephalic dopaminergic neurons from wild-type (WT) mice, and ERK signaling is significantly decreased in tyrosine hydroxylase (TH)-positive neurons in D2RϪ/Ϫ mice [7]
In mesencephalic neurons from WT mice, treatment with the D2R agonist quinpirole resulted in ERK activation, which was suppressed by pretreatment with AG1478 (Fig. 1A)
Summary
Dopamine D2R-mediated ERK activation regulates dopaminergic neuronal development. Results: D2R activation induces shedding of heparin-binding EGF by activating a disintegrin and metalloproteinase (ADAM) 10 or 17, causing EGFR transactivation in mesencephalic neurons. Conclusion: D2R-mediated ERK activation regulates mesencephalic dopaminergic neuron development via EGFR transactivation through ADAM10/17. We demonstrate that D2R induces the shedding of heparin-binding epidermal growth factor (EGF) through the activation of a disintegrin and metalloprotease (ADAM) 10 or 17, leading to EGF receptor transactivation, downstream ERK activation, and an increase in the number of dopaminergic neurons and their neurite length in primary mesencephalic cultures from wild-type mice. These outcomes, were not observed in cultures from D2R knock-out mice. We found that D2R-mediated transactivation of EGFR is critical for D2R-mediated ERK activation and for D2Rmediated control of dopaminergic neuron development
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