Alés Eva, Gullo Francesca, Arias Esperanza, Olivares Román, García Antonio G, Wanke Enzo, López Manuela G
Instituto Teófilo Hernando. Departamento de Farmacología y Terapéutica, Facultad de Medicina, U.A.M., Universidad Autónoma de Madrid, C/, Arzobispo Morcillo 4, E-28029 Madrid - Spain.
Eur J Pharmacol. 2006 Oct 24;548(1-3):45-52. doi: 10.1016/j.ejphar.2006.07.032. Epub 2006 Jul 28.
Galantamine is a drug in clinical use for the treatment of Alzheimer's disease, but its mechanism(s) of action remains controversial. Here we addressed the question whether galantamine could potentiate neurotransmitter release by inhibiting small conductance Ca2+ -activated K+ channels (KCa2). Galantamine potentiated catecholamine secretory responses induced by 10 s pulses of acetylcholine and high [K+]o applied to fast-superfused bovine adrenal chromaffin cell populations. Catecholamine release was significantly enhanced by galantamine although we did not find concentration dependence in the range 0.1-1 microM. The KCa2 channel blocker apamin (0.3 microM) occluded the potentiating effects of galantamine on acetylcholine-evoked secretion. Like apamin, galantamine also modified the firing of action potentials, but to a lesser extent. In addition, 1 microM galantamine reduced by 41% the KCa2 current without modifying the voltage-dependent Ca2+ currents. These results constitute the first direct evidence that galantamine can potentiate neurotransmitter release by blocking KCa2 channels, in addition to its already demonstrated capacity to mildly block acetylcholinesterase or potentiate allosterically nicotinic receptors.
加兰他敏是一种临床上用于治疗阿尔茨海默病的药物，但其作用机制仍存在争议。在这里，我们探讨了加兰他敏是否可以通过抑制小电导钙激活钾通道（KCa2）来增强神经递质释放的问题。加兰他敏增强了施加于快速灌流的牛肾上腺嗜铬细胞群体的10秒乙酰胆碱脉冲和高[K+]o诱导的儿茶酚胺分泌反应。尽管我们在0.1 - 1微摩尔范围内未发现浓度依赖性，但加兰他敏显著增强了儿茶酚胺释放。KCa2通道阻滞剂蜂毒明肽（0.3微摩尔）消除了加兰他敏对乙酰胆碱诱发分泌的增强作用。与蜂毒明肽一样，加兰他敏也改变了动作电位的发放，但程度较小。此外，1微摩尔加兰他敏使KCa2电流降低了41%，而不改变电压依赖性钙电流。这些结果构成了首个直接证据，表明加兰他敏除了已证实的轻度抑制乙酰胆碱酯酶或变构增强烟碱样受体的能力外，还可以通过阻断KCa2通道来增强神经递质释放。
