Department of Pharmacy, DiFAR, Center of Excellence for Biomedical Research, Viale Cembrano 4, 16148, University of Genoa, Genoa, Italy.
Department of Pharmacy, DiFAR, Center of Excellence for Biomedical Research, Viale Cembrano 4, 16148, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Neurochem Int. 2019 Jun;126:59-63. doi: 10.1016/j.neuint.2019.03.003. Epub 2019 Mar 8.
We investigated the impact of the prolonged exposure of rat hippocampal synaptosomes to CXCL12 (3 nM) on the NMDA-mediated release of [H]D-aspartate ([H]D-Asp) or [H]noradrenaline ([H]NA). Synaptosomes were stimulated twice with NMDA/CXCL12 and the amount of the NMDA-evoked tritium release (S1 and S2) quantified to calculate the S2/S1 ratio. The S2/S1 ratio for both transmitters was drastically decreased by 3 nM CXCL12 between the two stimuli (CXCL12-treated synaptosomes) in a AMD3100-sensitive manner. The phosphorylation of the GluN1 subunit in Ser 896 was reduced in CXCL12-treated synaptosomes, while the overall amount of GluN1 and GluN2B proteins as well as the GluN2B insertion in synaptosomal plasmamembranes were unchanged. We conclude that the CXCR4/NMDA cross-talk is dynamically regulated by the time of activation of the CXCR4s. Our results unveil a functional cross-talk that might account for the severe impairments of central transmission that develop in pathological conditions characterized by CXCL12 overproduction.
我们研究了 CXCL12（3nM）对大鼠海马突触体的长时间暴露对 NMDA 介导的[H]D-天冬氨酸([H]D-Asp)或[H]去甲肾上腺素([H]NA)释放的影响。突触体用 NMDA/CXCL12 刺激两次，并定量测量 NMDA 诱发的氚释放量（S1 和 S2），以计算 S2/S1 比值。两种递质的 S2/S1 比值在两次刺激（CXCL12 处理的突触体）之间均明显降低，且对 AMD3100 敏感。CXCL12 处理的突触体中 GluN1 亚基在 Ser896 的磷酸化减少，而 GluN1 和 GluN2B 蛋白的总量以及 GluN2B 在突触体质膜中的插入均无变化。我们的结论是，CXCR4/NMDA 相互作用是由 CXCR4 激活的时间动态调节的。我们的结果揭示了一种功能上的相互作用，它可能解释了在以 CXCL12 过度产生为特征的病理条件下中枢传递出现严重障碍的原因。
