Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia
Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia
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DOI：
10.1523/jneurosci.0837-12.2012
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发表时间：
2012-04-25
影响因子：
5.3
通讯作者：
Herve, Denis
中科院分区：
文献类型：
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作者：
Alcacer, Cristina;Santini, Emanuela;Herve, Denis
虽然L-3，4-二羟基苯丙氨酸（L-DOPA）仍然是帕金森病的参考治疗，但其长期有益作用受到L-DOPA诱导的运动障碍（LID）的阻碍。在多巴胺（DA）去神经支配的纹状体中，L-DOPA激活DA D-1受体（D1 R）信号传导，包括cAMP依赖性蛋白激酶A（PKA）和细胞外信号调节激酶（ERK），这两种反应与LID相关。然而，PKA和ERK激活的原因，它们各自对LID的贡献以及它们之间的关系尚不清楚。在纹状体神经元中，D1 R通过G α（olf）激活腺苷酸环化酶，这是一种在大鼠和患者中DA神经元损伤后上调的蛋白质。我们在这里报告，增加G α（olf）水平在偏侧帕金森病小鼠与LID慢性左旋多巴治疗后。为了确定这种上调的作用，我们在缺乏编码G α（olf）的Gnal基因的一个等位基因（Gnal（+/-））的小鼠中进行单侧损伤。尽管在受损的纹状体增加，G α（olf）水平仍然低于未受损的野生型小鼠。在Gnal（+/-）小鼠中，损伤诱导的L-DOPA对cAMP/PKA介导的GluA 1 Ser 845和DARPP-32（32 kDa DA和cAMP调节的磷蛋白）Thr 34磷酸化的刺激显著降低，而ERK激活被保留。L-DOPA（20 mg/kg）治疗10天后，Gnal（+/+）和Gnal（+/-）小鼠的LID发生率相似。因此，在病变动物中，G α（olf）上调对于D1 R刺激的cAMP/PKA而不是ERK信号的L-DOPA激活是关键的。虽然cAMP/PKA通路似乎是LID发展所必需的，但我们的研究结果表明，它的激活不太可能是LID的主要来源。相反，L-DOPA诱导的ERK激活在Gnal（+/-）小鼠中的持续性支持其在LID发展中的因果作用。
Although L-3,4-dihydroxyphenylalanine (L-DOPA) remains the reference treatment of Parkinson's disease, its long-term beneficial effects are hindered by L-DOPA-induced dyskinesia (LID). In the dopamine (DA)-denervated striatum, L-DOPA activates DA D-1 receptor (D1R) signaling, including cAMP-dependent protein kinase A (PKA) and extracellular signal-regulated kinase (ERK), two responses associated with LID. However, the cause of PKA and ERK activation, their respective contribution to LID, and their relationship are not known. In striatal neurons, D1R activates adenylyl-cyclase through G alpha(olf), a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased G alpha(olf) levels in hemiparkinsonian mice are correlated with LID after chronic L-DOPA treatment. To determine the role of this upregulation, we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for G alpha(olf) (Gnal (+/-)). Despite an increase in the lesioned striatum, G alpha(olf) levels remained below those of unlesioned wild-type mice. In Gnal (+/-) mice, the lesion-induced L-DOPA stimulation of cAMP/PKA-mediated phosphorylation of GluA1 Ser845 and DARPP-32 (32 kDa DA- and cAMP-regulated phosphoprotein) Thr34 was dramatically reduced, where as ERK activation was preserved. LID occurrence was similar in Gnal (+/+) and Gnal (+/-) mice after a 10-d L-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, G alpha(olf) upregulation is critical for the activation by L-DOPA of D1R-stimulated cAMP/PKA but not ERK signaling. Although the cAMP/PKA pathway appears to be required for LID development, our results indicate that its activation is unlikely to be the main source of LID. In contrast, the persistence of L-DOPA induced ERK activation in Gnal (+/-) mice supports its causal role in LID development.