CA/CALMODULIN-DEPENDENT KINASE-II INHIBITOR KN62 ATTENUATES GLUTAMATE RELEASE BY INHIBITING VOLTAGE-DEPENDENT CA2+-CHANNELS
CA/CALMODULIN-DEPENDENT KINASE-II INHIBITOR KN62 ATTENUATES GLUTAMATE RELEASE BY INHIBITING VOLTAGE-DEPENDENT CA2+-CHANNELS
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DOI：
10.1016/0028-3908(95)00051-7
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发表时间：
1995-07-01
影响因子：
4.7
通讯作者：
PEARSON, HA
中科院分区：
文献类型：
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作者：
SIHRA, TS;PEARSON, HA
本文观察了钙/钙调素依赖性激酶Ⅱ（Ca/CaM-K Ⅱ）抑制剂KN 62（1-[N，O-双（5-异喹啉磺酰基）-N-甲基-L-酪氨酰]-4-苯基哌嗪）对离体神经末梢（突触体）谷氨酸释放的影响。该药物引起了一个有效的抑制KCl和4-氨基吡啶诱发的谷氨酸释放从孤立的神经末梢（突触体）。抑制剂对Ca 2+内流的影响的检查显示，谷氨酸释放的减少可归因于胞质Ca的减少。KN 62对突触体Ca 2+通道的直接影响在实验中得到证实，其中使用不支持CaM依赖性过程的Ba代替Ca。此外，小脑颗粒神经元的全细胞膜片钳直接证明了KN 62对钙电流的抑制。因此，我们建议，在细胞系统中，基于使用KN 62作为Ca/CaM-K II阻滞剂的结论可能是模糊的，应谨慎看待，除非药物对Ca-内流的影响也被量化。KN 62对Ca 2+内流的影响似乎是特定于缓慢或非失活电导的，因此KN 62在这种情况下是一个潜在有用的工具。
The effect of KN62 (1-[N,O-bis(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiper azine), a putative inhibitor of Ca/calmodulin-dependent kinase II (Ca/CaM-K II), on glutamate release from isolated nerve-terminals (synaptosomes) was examined. The drug caused a potent inhibition of KCl- and 4-aminopyridine-evoked glutamate release from isolated nerve-terminals (synaptosomes). Examination of the effect of the inhibitor on Ca2+-influx revealed that the diminution of glutamate release could be attributed to a decrease in cytosolic Ca. A direct effect of KN62 on synaptosomal Ca2+-channels was confirmed in experiments where Ba, which does not support CaM-dependent processes, was used in place of Ca. Additionally, whole-cell patch-clamping of cerebellar granule neurones directly demonstrated inhibition of Ca-currents by KN62. We therefore suggest that, in cellular systems, conclusions based on the use of KN62 as a Ca/CaM-K II blocker may be ambiguous and should be viewed with caution unless the effect of the drug on Ca-influx has also been quantified. The effect of KN62 on Ca2+-influx appears to be specific to slowly- or non-inactivating conductances, and therefore presents KN62 as a potentially useful tool in this context.