Activation of UTP-Sensitive P2Y2 Receptor Induces the Expression of Cholinergic Genes in Cultured Cortical Neurons: A Signaling Cascade Triggered by Ca2+ Mobilization and Extracellular Regulated Kinase Phosphorylation
Activation of UTP-Sensitive P2Y2 Receptor Induces the Expression of Cholinergic Genes in Cultured Cortical Neurons: A Signaling Cascade Triggered by Ca2+ Mobilization and Extracellular Regulated Kinase Phosphorylation
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DOI：
10.1124/mol.112.084160
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发表时间：
2013-07-01
影响因子：
3.6
通讯作者：
Tsim, Karl W. K.
中科院分区：
文献类型：
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作者：
Choi, Roy C. Y.;Chu, Glanice K. Y.;Tsim, Karl W. K.
ATP 作为细胞外信号分子，与中枢和外周神经元突触的神经递质共同储存和共同释放。 ATP 刺激通过 P2Y 受体 (P2YR) 上调肌肉中突触基因的表达，包括尼古丁乙酰胆碱受体（α、δ 和 ε 亚基）和乙酰胆碱酯酶 (AChE) 的基因，但神经元对 P2YR 激活的营养反应尚不清楚。我们报道培养的皮质神经元和发育中的大鼠大脑表达不同类型的P2YR，其中UTP敏感的P2Y(2)R最为丰富。发现 P2Y(2)R 存在于膜筏中，并与皮层神经元中的突触后蛋白 PSD-95 共定位。值得注意的是，P2Y(2)R 的激动剂依赖性刺激提高了编码 AChE、PRiMA（球状形式 AChE 的锚）和胆碱乙酰转移酶的胆碱能基因的神经元表达，并且这种诱导是由涉及 Ca2+ 动员和细胞外调节激酶 1/2 激活的信号级联介导的。 P2Y(2)R 受体与 P2Y(1)R 的协同作用进一步证明了 P2Y(2)R 作用的重要性，通过强力刺激 Ca2+ 流入来增强胆碱能基因表达。总而言之，我们的结果揭示了 P2Y(2)R 在促进突触基因表达中的发育功能，并证明了 P2Y(1)R 和 P2Y(2)R 在神经元中共刺激的影响。
ATP functions as an extracellular signaling molecule that is costored and coreleased with neurotransmitters at central and peripheral neuronal synapses. Stimulation by ATP upregulates the expression of synaptic genes in muscle-including the genes for nicotine acetylcholine receptor (alpha-, delta-, and epsilon-subunits) and acetylcholinesterase (AChE)-via the P2Y receptor (P2YR), but the trophic response of neurons to the activation of P2YRs is less well understood. We reported that cultured cortical neurons and the developing rat brain expressed different types of P2YRs, and among these the UTP-sensitive P2Y(2)R was the most abundant. P2Y(2)R was found to exist in membrane rafts and it colocalized with the postsynaptic protein PSD-95 in cortical neurons. Notably, agonist-dependent stimulation of P2Y(2)R elevated the neuronal expression of cholinergic genes encoding AChE, PRiMA (an anchor for the globular form AChE), and choline acetyltransferase, and this induction was mediated by a signaling cascade that involved Ca2+ mobilization and extracellular regulated kinases 1/2 activation. The importance of P2Y(2)R action was further shown by the receptor's synergistic effect with P2Y(1)R in enhancing cholinergic gene expression via the robust stimulation of Ca2+ influx. Taken together our results revealed a developmental function of P2Y(2)R in promoting synaptic gene expression and demonstrated the influence of costimulation of P2Y(1)R and P2Y(2)R in neurons.