Moriguchi Shigeki, Shioda Norifumi, Han Feng, Yeh Jay Z, Narahashi Toshio, Fukunaga Kohji
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.
Hippocampus. 2009 Sep;19(9):844-54. doi: 10.1002/hipo.20572.
Galantamine, a novel Alzheimer's drug, is known to inhibit acetylcholinesterase activity and potentiate nicotinic acetylcholine receptor (nAChR) in the brain. We previously reported that galantamine potentiates the NMDA-induced currents in primary cultured rat cortical neurons. We now studied the effects of galantamine on long-term potentiation (LTP) in the rat hippocampal CA1 regions. The field excitatory postsynaptic potentials (fEPSPs) were induced by stimulation of the Schaffer collateral/commissural pathways in the hippocampal CA1 region. Treatment with 0.01-10 microM galantamine did not affect the slope of fEPSPs in the CA1 region. Galantamine treatment increased calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase Calpha (PKCalpha) activities with a bell-shaped dose-response curve peaked at 1 microM, thereby increasing the phosphorylation of AMPA receptor, myristoylated alanine-rich protein kinase C, and NMDA receptor as downstream substrates of CaMKII and/or PKCalpha. By contrast, galatamine treatment did not affect protein kinase A activity. Consistent with the bell-shaped CaMKII and PKCalpha activation, galantamine treatment enhanced LTP in the hippocampal CA1 regions with the same bell-shaped dose-response curve. Furthermore, LTP potentiation induced by galantamine treatment at 1 microM was closely associated with both CaMKII and PKC activation with concomitant increase in phosphorylation of their downstream substrates except for synapsin I. In addition, the enhancement of LTP by galantamine was accompanied with alpha7-type nAChR activation. These results suggest that galantamine potentiates NMDA receptor-dependent LTP through alpha7-type nAChR activation, by which the postsynaptic CaMKII and PKC are activated.
加兰他敏是一种新型抗阿尔茨海默病药物，已知其可抑制大脑中的乙酰胆碱酯酶活性并增强烟碱型乙酰胆碱受体（nAChR）功能。我们之前报道过加兰他敏可增强原代培养大鼠皮层神经元中NMDA诱导的电流。我们现在研究了加兰他敏对大鼠海马CA1区长期增强（LTP）的影响。通过刺激海马CA1区的Schaffer侧支/连合通路诱导场兴奋性突触后电位（fEPSP）。用0.01 - 10 microM加兰他敏处理并未影响CA1区fEPSP的斜率。加兰他敏处理使钙/钙调蛋白依赖性蛋白激酶II（CaMKII）和蛋白激酶Cα（PKCα）的活性增加，呈钟形剂量反应曲线，在1 microM时达到峰值，从而增加了作为CaMKII和/或PKCα下游底物的AMPA受体、肉豆蔻酰化富含丙氨酸的蛋白激酶C和NMDA受体的磷酸化。相比之下，加兰他敏处理不影响蛋白激酶A的活性。与钟形的CaMKII和PKCα激活一致，加兰他敏处理增强了海马CA1区的LTP，具有相同的钟形剂量反应曲线。此外，1 microM加兰他敏处理诱导的LTP增强与CaMKII和PKC的激活密切相关，同时其下游底物（除突触结合蛋白I外）的磷酸化增加。此外，加兰他敏对LTP的增强伴随着α7型nAChR的激活。这些结果表明，加兰他敏通过激活α7型nAChR增强NMDA受体依赖性LTP，由此激活突触后CaMKII和PKC。
