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首页> 外文期刊>The European Journal of Neuroscience >Dopamine D(2) receptors regulate tyrosine hydroxylase activity and phosphorylation at Ser40 in rat striatum.
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Dopamine D(2) receptors regulate tyrosine hydroxylase activity and phosphorylation at Ser40 in rat striatum.

机译：多巴胺D（2）受体调节大鼠纹状体中酪氨酸羟化酶活性和Ser40的磷酸化。

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摘要

In the striatum, dopamine release is inhibited by activation of dopamine D(2) autoreceptors. Changes in dopamine release have been attributed to changes in the synthesis of dopamine, which is regulated via phosphorylation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines. Here, we have studied the involvement of dopamine D(2) receptors in the regulation of TH phosphorylation at distinct seryl residues, using phosphorylation site-specific antibodies and a preparation of rat striatal slices. The D(2) receptor agonist, quinpirole, reduced basal TH phosphorylation at Ser40 but not at Ser19 or Ser31. Quinpirole was also able to reduce the increase in Ser40 phosphorylation caused by forskolin, an activator of adenylyl cyclase, without affecting the increase in Ser19 phosphorylation produced by the glutamate receptor agonist, N-methyl-D-aspartate (NMDA). In addition, the dopamine D(2) receptor agonist reduced both basal and forskolin-stimulated activity of TH, measured as 3,4-dihydroxyphenylalanine (DOPA) accumulation. Quinpirole decreased phosphorylation of Ser40 induced by okadaic acid, an inhibitor of protein phosphatase 1 and 2A and Ro-20-1724, a phosphodiesterase inhibitor. In contrast, quinpirole did not affect the increase in Ser40 phosphorylation caused by the cAMP analogue, 8-Br-cAMP. These data indicate that, in the striatum, activation of dopamine D(2) receptors results in selective inhibition of TH phosphorylation at Ser40 via reduction of the activity of adenylyl cyclase. They also provide a molecular mechanism accounting for the ability of dopamine D(2) autoreceptors to inhibit dopamine synthesis and release from nigrostriatal nerve terminals.
机译：在纹状体中，多巴胺释放被多巴胺D（2）自身受体激活抑制。多巴胺释放的变化归因于多巴胺合成的变化，该变化通过酪氨酸羟化酶（TH）（儿茶酚胺合成中的限速酶）的磷酸化来调节。在这里，我们使用磷酸化位点特异性抗体和大鼠纹状体切片的制备，研究了多巴胺D（2）受体参与不同丝氨酸残基TH磷酸化的调节。 D（2）受体激动剂喹吡罗减少了Ser40的基础TH磷酸化，但没有降低Ser19或Ser31的基础TH磷酸化。喹吡罗还能够减少由福司可林（腺苷酸环化酶的活化剂）引起的Ser40磷酸化的增加，而不会影响谷氨酸受体激动剂N-甲基-D-天冬氨酸（NMDA）产生的Ser19磷酸化的增加。此外，多巴胺D（2）受体激动剂可降低3，4-二羟基苯丙氨酸（DOPA）积累的基础和福斯高林刺激的TH活性。喹吡罗减少了由冈田酸（一种蛋白磷酸酶1和2A的抑制剂）和Ro-20-1724（一种磷酸二酯酶的抑制剂）诱导的Ser40的磷酸化。相反，喹吡罗不会影响由cAMP类似物8-Br-cAMP引起的Ser40磷酸化的增加。这些数据表明，在纹状体中，多巴胺D（2）受体的激活通过降低腺苷酸环化酶的活性，选择性抑制Ser40处的TH磷酸化。他们还提供了解释多巴胺D（2）自体受体抑制多巴胺合成和从黑纹状体神经末梢释放的能力的分子机制。

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