NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats
NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats
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DOI：
10.1007/s001250051217
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发表时间：
1999-06-01
期刊：
影响因子：
8.2
通讯作者：
Gispen, WH
中科院分区：
文献类型：
--
作者：
Di Luca, M;Ruts, L;Gispen, WH
目的/假说。中度学习和记忆障碍被认为是糖尿病患者的并发症。链脲佐菌素糖尿病大鼠是胰岛素依赖型糖尿病的动物模型，其空间记忆和长时程增强表达出现损伤。我们研究了实验性糖尿病对突触后谷氨酸n -甲基- d -天冬氨酸离子化受体和其他调节突触后区室突触传递的关键蛋白表达的影响。采用原位杂交和Western blot检测n-甲基-d -天冬氨酸受体和α -钙-钙调素依赖性激酶II的表达和蛋白浓度。研究了受体亚单位α camkii依赖性磷酸化在对照组、链脲佐菌素糖尿病和胰岛素治疗大鼠海马和皮质突触后密度的变化。与年龄匹配的对照组大鼠相比，n -甲基- d -天冬氨酸NR1和NR2A亚基的转录水平在糖尿病持续3个月的大鼠中没有变化。因此，NR1和NR2A以及GluR1、GluR2/3、PSD-95和α - CaMKII蛋白在对照和糖尿病大鼠突触后密度中的浓度相同，而NR2B的免疫反应性降低了约40%。此外，与对照大鼠相比，α - CaMKII对外源性底物（如synpeptide -2）的活性和n-甲基-d -天冬氨酸受体NR2A/B亚基的磷酸化在链脲霉素糖尿病大鼠海马突触后密度中降低。此外，我们发现在糖尿病持续3个月后进行胰岛素干预可以部分恢复aCaMKII活性和NR2B水平。n-甲基-d -天冬氨酸受体的表达和磷酸化可能参与了链脲佐菌素糖尿病大鼠的行为和电生理异常。
Aims/hypothesis. Moderate disturbances of learning and memory were recognized as a complication of diabetes mellitus in patients. The streptozotocin-diabetic rat, an animal model of insulin-dependent diabetes, shows impairments in spatial memory and in long-term potentiation expression. We have studied the effect of experimental diabetes on expression of post-synaptic glutamate N-Methyl-D-Aspartate ionotropic receptors and of other key proteins regulating synaptic transmission at the post-synaptic compartment.Methods. In situ hybridization and Western blot analysis were used to assess expression and protein concentration of N-Methyl-D-Aspartate receptors and alpha-calcium-calmodulin-dependent kinase II. Receptor subunits alpha CaMKII-dependent phosphorylation was studied in post-synaptic densities obtained from the hippocampus and cortex of control, streptozotocin-diabetic and insulin-treated rats.Results. The transcript levels of NR1 and NR2A subunits of N-Methyl-D-Aspartate were unchanged in rats with a diabetic duration of 3 months when compared with age-matched control rats. Accordingly, NR1 and NR2A as well as GluR1, GluR2/3, PSD-95 and alpha CaMKII protein concentrations in post-synaptic densities were the same in both control and diabetic rats, whereas the immunoreactivity for NR2B was reduced by about 40 %. In addition, the activity of alpha CaMKII on exogenous substrates, such as syntide-2, and the phosphorylation of NR2A/B subunits of N-Methyl-D-Aspartate receptor was reduced in hippocampal post-synaptic densities of streptozotocin-diabetic rats as compared with control rats. Furthermore, we show that insulin intervention for 3 months after diabetic duration partially restored both aCaMKII activity and NR2B levels.Conclusion/interpretation. N-Methyl-D-Aspartate receptor expression and phosphorylation is possibly involved in behavioural and electrophysiological abnormalities observed in streptozotocin-diabetic rats.