1. Role of adrenoceptors in the regulation of dopamine/DARPP-32 signaling in neostriatal neurons.
- Author
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Hara M, Fukui R, Hieda E, Kuroiwa M, Bateup HS, Kano T, Greengard P, and Nishi A
- Subjects
- Adrenergic alpha-2 Receptor Antagonists, Animals, Catalytic Domain drug effects, Catalytic Domain physiology, Cyclic AMP Response Element-Binding Protein metabolism, Dopamine and cAMP-Regulated Phosphoprotein 32 drug effects, GTP-Binding Protein alpha Subunits, Gi-Go drug effects, GTP-Binding Protein alpha Subunits, Gi-Go metabolism, Male, Mice, Mice, Inbred C57BL, Neostriatum drug effects, Neurons drug effects, Organ Culture Techniques, Parkinson Disease drug therapy, Parkinson Disease metabolism, Parkinson Disease physiopathology, Phosphorylation drug effects, Receptor, Adenosine A2A drug effects, Receptor, Adenosine A2A metabolism, Receptors, Adrenergic drug effects, Receptors, Adrenergic, alpha-2 metabolism, Receptors, Adrenergic, beta-1 drug effects, Receptors, Adrenergic, beta-1 metabolism, Receptors, Dopamine D2 drug effects, Receptors, Dopamine D2 metabolism, Signal Transduction drug effects, Signal Transduction physiology, Threonine metabolism, Dopamine metabolism, Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism, Neostriatum metabolism, Neurons metabolism, Receptors, Adrenergic metabolism
- Abstract
Studies in animal models of Parkinson's disease have revealed that degeneration of noradrenaline neurons is involved in the motor deficits. Several types of adrenoceptors are highly expressed in neostriatal neurons. However, the selective actions of these receptors on striatal signaling pathways have not been characterized. In this study, we investigated the role of adrenoceptors in the regulation of dopamine/dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) signaling by analyzing DARPP-32 phosphorylation at Thr34 [protein kinase A (PKA)-site] in mouse neostriatal slices. Activation of beta(1)-adrenoceptors induced a rapid and transient increase in DARPP-32 phosphorylation. Activation of alpha(2)-adrenoceptors also induced a rapid and transient increase in DARPP-32 phosphorylation, which subsequently decreased below basal levels. In addition, activation of alpha(2)-adrenoceptors attenuated, and blockade of alpha(2)-adrenoceptors enhanced dopamine D(1) and adenosine A(2A) receptor/DARPP-32 signaling. Chemical lesioning of noradrenergic neurons mimicked the effects of alpha(2)-adrenoceptor blockade. Under conditions of alpha(2)-adrenoceptor blockade, the dopamine D(2) receptor-induced decrease in DARPP-32 phosphorylation was attenuated. Our data demonstrate that beta(1)- and alpha(2)-adrenoceptors regulate DARPP-32 phosphorylation in neostriatal neurons. G(i) activation by alpha(2)-adrenoceptors antagonizes G(s)/PKA signaling mediated by D(1) and A(2A) receptors in striatonigral and striatopallidal neurons, respectively, and thereby enhances D(2) receptor/G(i) signaling in striatopallidal neurons. alpha(2)-Adrenoceptors may therefore be a therapeutic target for the treatment of Parkinson's disease.
- Published
- 2010
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