Selective blockade of N-type calcium channels by levetiracetam
Selective blockade of N-type calcium channels by levetiracetam
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DOI：
10.1046/j.1528-1157.2002.24501.x
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发表时间：
2002-01-01
期刊：
影响因子：
5.6
通讯作者：
Kostyuk, PG
中科院分区：
文献类型：
--
作者：
Lukyanetz, EA;Shkryl, VM;Kostyuk, PG
目的：本研究观察了新型抗癫痫药物左乙拉西坦（levetiracetam，LEV）对大鼠海马CA 1区神经元不同类型高电压激活（high-voltage-activated，HVA）Ca ~（2+）通道的影响。LEV通过重力流从放置在细胞附近的移液管施加，并且通过电动微阀进行溶液改变。结果：在对照组和应用1-200 μ M LEV后，测量了电流。LEV不可逆地抑制HVA钙电流，平均抑制率约为18%。用一种能消除G蛋白对Ca ~（2+）通道的直接抑制作用的预脉冲刺激方案，我们发现G蛋白不参与LEV抑制效应的潜在途径。这表明，抑制作用来自LEV对通道分子的直接作用。LEV的阻断机制与Ca 2+通道稳态激活或失活的变化无关。LEV也没有影响的HVA钙电流在实验过程中持续类似的10分钟。最后，LEV在使用的最高浓度（200 μ M）不影响CAI神经元中的L-，P-或Q-型钙通道的活性，而选择性地影响N-型钙通道的活性。结论：LEV选择性抑制CAI区海马锥体神经元N型钙通道。这些数据表明，存在一个亚型的N型通道敏感LEV，这可能是参与其抗癫痫作用的分子基础。
Purpose: We investigated the effect of the new antiepileptic drug (AED) levetiracetam (LEV) on different types of high-voltage-activated (HVA) Ca2+ channels in freshly isolated CA I hippocampal neurons of rats.Methods: Patch-clamp recordings of HVA Ca2+ channel activity were obtained from isolated hippocampal CAI neurons. LEV was applied by gravity flow from a pipette placed near the cell, and solution changes were made by electromicrovalves. Ca2+ channel blockers were used for separation of the channel subtypes.Results: The currents were measured in controls and after application of 1-200 muM LEV. LEV irreversibly inhibited the HVA calcium current by similar to18% on the average. With a prepullse stimulation protocol, which can eliminate direct inhibition of Ca2+ channels by G proteins, we found that G proteins were not involved in the pathways underlying the LEV inhibitory effect. This suggested that the inhibitory effect arises from a direct action of LEV on the channel molecule. The blocking mechanism of LEV was not related to changes in steady-state activation or inactivation of Ca2+ channels. LEV also did not influence the rundown of the HVA Ca2+ current during experimental protocols lasting similar to10 min. Finally, LEV at the highest concentration used (200 muM) did not influence the activity of L-, P- or Q-type Ca2+ channels in CAI neurons, while selectively influencing the activity of N-type calcium channels. The maximal effect on these channels separated from other channel types was -similar to37%.Conclusions: Our results provide evidence that LEV selectively inhibits N-type Ca2+ channels of CAI pyramidal hippocampal neurons. These data suggest the existence of a subtype of N-type channels sensitive to LEV, which might be involved in the molecular basis of its antiepileptic action.