Maguire C, Casey M, Kelly A, Mullany P M, Lynch M A
Physiology Department, Trinity College, Dublin, Ireland.
Hippocampus. 1999;9(5):519-26. doi: 10.1002/(SICI)1098-1063(1999)9:5<519::AID-HIPO5>3.0.CO;2-Y.
Long-term potentiation (LTP) in perforant path-granule cell synapses has been shown to be accompanied by an increase in glutamate release. The objective of this study was to examine the possibility that nerve growth factor (NGF), by activating tyrosine kinase, modulates glutamate release and, therefore, contributes to expression of LTP in dentate gyrus. The data indicate that NGF, in the presence of trans-1-aminocyclopentyl-1,3-dicarboxylate (ACPD), enhanced KCI-stimulated release and KCI-stimulated calcium influx in vitro and that these effects were blocked by the tyrosine receptor kinase (trk) inhibitor tyrphostin AG879. The data also indicate that NGF increased phosphorylation of trkA and the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) in dentate gyrus in vitro. In addition to its effects in vitro, tyrphostin AG879 inhibited the expression of LTP in perforant path-granule cell synapses and the accompanying increase in transmitter release. Analysis of phosphorylation of the two tyrosine kinase substrates trkA and ERK in synaptosomes prepared from untetanized and tetanized dentate gyrus revealed that LTP was associated with increased phosphorylation of both proteins; no evidence of such a change was observed in either tetanized or untetanized tissue prepared from tyrphostin-pretreated rats. These findings are consistent with the hypothesis that NGF, by interacting with trkA, triggers a sequence of tyrosine kinase-dependent phosphorylation steps that modulate glutamate release and calcium influx and impact on expression of LTP in dentate gyrus.
在穿通通路-颗粒细胞突触中，长期增强效应（LTP）已被证明伴随着谷氨酸释放的增加。本研究的目的是检验神经生长因子（NGF）通过激活酪氨酸激酶来调节谷氨酸释放，从而促进齿状回中LTP表达的可能性。数据表明，在反式-1-氨基环戊基-1,3-二羧酸（ACPD）存在的情况下，NGF在体外增强了氯化钾刺激的释放和氯化钾刺激的钙内流，并且这些效应被酪氨酸受体激酶（trk）抑制剂 tyrphostin AG879所阻断。数据还表明，NGF在体外增加了齿状回中trkA和丝裂原活化蛋白激酶细胞外信号调节激酶（ERK）的磷酸化。除了其体外效应外，tyrphostin AG879还抑制了穿通通路-颗粒细胞突触中LTP的表达以及随之而来的递质释放增加。对从未经强直刺激和经强直刺激的齿状回制备的突触体中两种酪氨酸激酶底物trkA和ERK的磷酸化分析表明，LTP与这两种蛋白的磷酸化增加有关；在从tyrphostin预处理大鼠制备的经强直刺激或未经强直刺激的组织中均未观察到这种变化的证据。这些发现与以下假设一致，即NGF通过与trkA相互作用，触发一系列酪氨酸激酶依赖性磷酸化步骤，从而调节谷氨酸释放和钙内流，并影响齿状回中LTP的表达。
