Specific involvement of Ca(2+)-calmodulin kinase II in cholinergic modulation of neuronal responsiveness.
Specific involvement of Ca(2+)-calmodulin kinase II in cholinergic modulation of neuronal responsiveness.
复制标题
Ca(2)-钙调蛋白激酶 II 在神经元反应性胆碱能调节中的特异性参与。
DOI：
10.1152/jn.1992.68.6.2264
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发表时间：
1992
影响因子：
2.5
通讯作者：
Connor,JA
中科院分区：
文献类型：
--
作者：
Muller,W;Petrozzino,JJ;Griffith,LC;Danho,W;Connor,JA
1. 当低浓度的毒蕈碱激动剂应用于海马时，通过阻断 Ca(2+) 激活的 K 电导 gK (Ca) 来抑制对神经元兴奋性的内在控制，从而调节 CA1 和 CA3 神经元的放电适应和慢后超极化 (sAHP)。例如，卡巴胆碱在 0.1-0.3 µM 时有效，表明可激活相对高亲和力的受体。 2. 我们通过使用一种新的、高度特异性的 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 肽抑制剂以及其他激酶抑制剂，研究了这种作用的机制，并表明 gK (Ca) 的毒蕈碱阻滞依赖于 CA1 和 CA3 神经元中 CaMKII 的激活。因此，这些通道或中间蛋白的磷酸化导致通道在存在 Ca2+ 和去极化的情况下保持关闭。 3. 血清素能激动剂和谷氨酸能激动剂非常相似的电生理作用是通过其他激酶或完全不同的过程介导的。 4.冈田酸阻断内在磷酸酶活性也降低了适应性和sAHP，而毒蕈碱激动剂对这些量没有进一步影响。 5. 去除动物海马体的突触前胆碱能输入对于执行需要空间记忆的任务具有有害影响，并且还被认为是人类认知障碍的原因。通过增加电活动过程中 Ca2+ 的积累并促进 CaMKII 活性，毒蕈碱输入为诱导长期增强（一种重要的细胞记忆机制）提供了平行的增强途径。这表明学习和记忆分析的行为方法和细胞方法之间可能存在联系。
1. Muscarinic agonists when applied in the hippocampus at low concentrations suppress intrinsic controls on neuronal excitability through the block of Ca(2+)-activated K conductance(s), gK (Ca), underlying the adaptation of firing and slow afterhyperpolarization (sAHP) in CA1 and CA3 neurons. Carbachol, for example, is effective at 0.1-0.3 microM suggesting activation of a relatively high-affinity receptor. 2. We have examined the mechanism of this action by using a new, highly specific, peptide inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII) as well as other kinase inhibitors and show that the muscarinic block of gK (Ca) relies on CaMKII activation in both CA1 and CA3 neurons. Thus phosphorylation of these channels or of an intermediary protein causes the channels to remain closed in the presence of Ca2+ and depolarization. 3. The very similar electrophysiological effects of serotonergic and glutamatergic agonists are mediated either through other kinases or by entirely different processes. 4. Block of intrinsic phosphatase activity by okadaic acid also reduced adaptation and sAHP, and muscarinic agonists had no further effect on these quantities. 5. The removal of presynaptic cholinergic inputs to the hippocampus in animals has a deleterious effect on the performance of tasks requiring spatial memory and is also implicated as a cause of cognitive disorders in humans. By increasing Ca2+ accumulation during electrical activity and promoting CaMKII activity, muscarinic input provides parallel reinforcing pathways for the induction of long-term potentiation, an important cellular memory mechanism. This suggests a possible link between behavioral and cellular approaches to the analysis of learning and memory.