Inhibition of the ATP-gated P2X7 receptor promotes axonal growth and branching in cultured hippocampal neurons
Inhibition of the ATP-gated P2X7 receptor promotes axonal growth and branching in cultured hippocampal neurons
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DOI：
10.1242/jcs.034082
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发表时间：
2008-11-15
影响因子：
4
通讯作者：
Miras-Portugal, Maria Teresa
中科院分区：
文献类型：
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作者：
Diaz-Hernandez, Miguel;del Puerto, Ana;Miras-Portugal, Maria Teresa
在神经回路的建立过程中，神经元的轴突响应于正刺激和负刺激而向其目标区域生长。由于最近的报道表明，生长锥中的钙瞬变负调控轴突生长，我们研究了离子型ATP受体（P2X）可能参与这一过程。我们的研究结果表明，暴露培养的海马神经元ATP诱导Ca2+瞬变在轴突的远端域和轴突生长的伴随抑制。这种效应是由P2X7受体介导的，该受体存在于轴突的生长锥中。对P2 X7的药理学抑制或通过shRNA干扰使其沉默会诱导更长、分支更多的轴突，并伴有生长锥的形态变化。我们的数据表明，这些形态学的变化是由一个信号级联反应，其中CaMKII和FAK活性激活PI3激酶和修改其下游目标的活动。因此，在P2X7受体缺乏或失活的情况下，轴突在培养的海马神经元中生长更快，并形成更多的分支，表明ATP对轴突生长产生负面影响。这些数据表明P2X7拮抗剂具有促进轴突再生的治疗潜力。
During the establishment of neural circuits, the axons of neurons grow towards their target regions in response to both positive and negative stimuli. Because recent reports show that Ca2+ transients in growth cones negatively regulate axonal growth, we studied how ionotropic ATP receptors (P2X) might participate in this process. Our results show that exposing cultured hippocampal neurons to ATP induces Ca2+ transients in the distal domain of the axon and the concomitant inhibition of axonal growth. This effect is mediated by the P2X7 receptor, which is present in the growth cone of the axon. Pharmacological inhibition of P2X7 or its silencing by shRNA interference induces longer and more-branched axons, coupled with morphological changes to the growth cone. Our data suggest that these morphological changes are induced by a signalling cascade in which CaMKII and FAK activity activates PI3-kinase and modifies the activity of its downstream targets. Thus, in the absence or inactivation of P2X7 receptor, axons grow more rapidly and form more branches in cultured hippocampal neurons, indicative that ATP exerts a negative influence on axonal growth. These data suggest that P2X7 antagonists have therapeutic potential to promote axonal regeneration.