Activation of Adenosine A2A Receptors Induces TrkB Translocation and Increases BDNF-Mediated Phospho-TrkB Localization in Lipid Rafts: Implications for Neuromodulation (Retracted article. See vol. 33, pg. 1292, 2013)
Activation of Adenosine A2A Receptors Induces TrkB Translocation and Increases BDNF-Mediated Phospho-TrkB Localization in Lipid Rafts: Implications for Neuromodulation (Retracted article. See vol. 33, pg. 1292, 2013)
复制标题
DOI：
10.1523/jneurosci.5695-09.2010
复制
发表时间：
2010-06-23
影响因子：
5.3
通讯作者：
Sebastiao, Ana M.
中科院分区：
文献类型：
--
作者：
Assaife-Lopes, Natalia;Sousa, Vasco C.;Sebastiao, Ana M.
脑源性神经营养因子（BDNF）信号传导对神经元的发育和传递至关重要。TrkB受体在脂筏上的募集已被证明是激活特定信号通路和调节BDNF释放神经递质所必需的。由于已知TrkB受体受腺苷A（2A）受体激活的调节，我们假设A（2A）受体的激活可能影响TrkB受体在不同膜微域中的定位。我们发现腺苷A（2A）受体激动剂增加了皮质膜脂筏部分TrkB受体的水平，并增强了bdnf诱导的脂筏中磷酸化TrkB水平的增加。单丹糖cadaverine （100 μ M）阻断网格蛋白介导的内吞作用不会改变A（2A）受体激动剂的作用，但会显著削弱BDNF对TrkB向脂筏募集的作用。A（2A）受体激活对TrkB定位的影响用5 μ M的腺苷酸环化酶激活剂模拟。此外，PKA抑制剂Rp-cAMPs和PKI-(14-22)以及src家族激酶抑制剂PP2也能阻断它。此外，去除内源性腺苷或破坏脂筏可降低BDNF对皮层突触体谷氨酸释放的刺激作用。脂质筏完整性也是BDNF对海马CA1突触长期增强的影响所必需的。我们的数据首次证明，通过腺苷a （2A）受体的激活，bdnf诱导TrkB受体向脂质筏募集，具有TrkB磷酸化和bdnf诱导的神经递质释放和海马可塑性调节的功能后果。
Brain-derived neurotrophic factor (BDNF) signaling is critical for neuronal development and transmission. Recruitment of TrkB receptors to lipid rafts has been shown to be necessary for the activation of specific signaling pathways and modulation of neurotransmitter release by BDNF. Since TrkB receptors are known to be modulated by adenosine A(2A) receptor activation, we hypothesized that activation of A(2A) receptors could influence TrkB receptor localization among different membrane microdomains. We found that adenosine A(2A) receptor agonists increased the levels of TrkB receptors in the lipid raft fraction of cortical membranes and potentiated BDNF-induced augmentation of phosphorylated TrkB levels in lipid rafts. Blockade of the clathrin-mediated endocytosis with monodansylcadaverine (100 mu M) did not modify the effects of the A(2A) receptor agonists but significantly impaired BDNF effects on TrkB recruitment to lipid rafts. The effect of A(2A) receptor activation in TrkB localization was mimicked by 5 mu M forskolin, an adenylyl cyclase activator. Also, it was blocked by the PKA inhibitors Rp-cAMPs and PKI-(14-22), and by the Src-family kinase inhibitor PP2. Moreover, removal of endogenous adenosine or disruption of lipid rafts reduced BDNF stimulatory effects on glutamate release from cortical synaptosomes. Lipid raft integrity was also required for the effects of BDNF on hippocampal long-term potentiation at CA1 synapses. Our data demonstrate, for the first time, a BDNF-independent recruitment of TrkB receptors to lipid rafts induced by activation of adenosine A(2A) receptors, with functional consequences for TrkB phosphorylation and BDNF-induced modulation of neurotransmitter release and hippocampal plasticity.