Vatanparast Jafar, Janahmadi Mahyar, Asgari Ali Reza
Neuroscience Research Center and Department of Physiology, Faculty of Medicine, Shaheed Beheshti Medical Sciences University, Evin, P.O.Box 19835-181, Tehran, Iran.
Eur J Pharmacol. 2007 Oct 1;571(2-3):81-7. doi: 10.1016/j.ejphar.2007.06.008. Epub 2007 Jun 13.
We have previously reported that paraoxon, an organophosphate compound, at submicromolar concentrations effectively suppresses Ca2+ action potentials and modulates the activity of snail neurons. This effect was unrelated to acetylcholinesterase inhibition but was found to involve the direct or indirect modulation of ion channels [Vatanparast, J., Janahmadi, M., Asgari, A.R., Sepehri, H., Haeri-Rohani, A., 2006a. Paraoxon suppresses Ca2+ action potential and afterhyperpolarization in snail neurons: Relevance to the hyperexcitability induction. Brain Res. 1083 (1), 110-117]. In the present work, the interaction of paraoxon with protein kinase C (PKC) and inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release, on the modulation of Ca2+ action potentials and neuronal activity was investigated. Phorbol 12, 13 dibutyrate (PdBu), the activator of PKC, suppressed afterhyperpolarization and increased the activity of snail neurons without any significant effect on the Ca2+ action potential duration. Pretreatment with PKC activator attenuated the suppressing effect of paraoxon on the duration of Ca2+ action potentials. Staurosporine, a selective blocker of PKC, did not block the effect of paraoxon on Ca2+ action potential suppression and hyperexcitability induction. Our findings did not support the involvement PKC in the paraoxon induced Ca2+ action potential suppression and neuronal activity modulation, although activation of this protein kinase could attenuate some effects of paraoxon. Pretreatment with 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), an antagonist of IP3-mediated Ca2+ release, abolished the secondary silencing effect of paraoxon, which is observed after primary paraoxon-induced hyperexcitability. It was concluded that slow activation of intracellular cascades by paraoxon could induce an IP3 mediated Ca2+ release from intracellular stores and participate to its secondary silencing effect by mechanisms dependent on intracellular calcium homeostasis.
我们之前报道过，对氧磷（一种有机磷酸酯化合物）在亚微摩尔浓度下可有效抑制Ca2+动作电位并调节蜗牛神经元的活性。这种效应与乙酰胆碱酯酶抑制无关，但发现涉及离子通道的直接或间接调节[Vatanparast, J., Janahmadi, M., Asgari, A.R., Sepehri, H., Haeri-Rohani, A., 2006a. 对氧磷抑制蜗牛神经元中的Ca2+动作电位和超极化后电位：与兴奋性过高诱导的相关性。《脑研究》1083 (1), 110 - 117]。在本研究中，研究了对氧磷与蛋白激酶C（PKC）的相互作用以及肌醇1,4,5 - 三磷酸（IP3）介导的Ca2+释放对Ca2+动作电位和神经元活性调节的影响。PKC激活剂佛波醇12,13 - 二丁酸酯（PdBu）可抑制超极化后电位并增加蜗牛神经元的活性，而对Ca2+动作电位持续时间无任何显著影响。用PKC激活剂预处理可减弱对氧磷对Ca2+动作电位持续时间的抑制作用。PKC选择性阻滞剂星形孢菌素并未阻断对氧磷对Ca2+动作电位抑制和兴奋性过高诱导的作用。我们的研究结果不支持PKC参与对氧磷诱导的Ca2+动作电位抑制和神经元活性调节，尽管激活这种蛋白激酶可减弱对氧磷的一些作用。用IP3介导的Ca2+释放拮抗剂盐酸8 - （N,N - 二乙氨基）辛基 - 3,4,5 - 三甲氧基苯甲酸酯（TMB - 8）预处理可消除对氧磷的继发性沉默效应，该效应在对氧磷诱导的原发性兴奋性过高后出现。得出的结论是，对氧磷对细胞内级联反应的缓慢激活可诱导IP3介导的细胞内钙库Ca2+释放，并通过依赖细胞内钙稳态的机制参与其继发性沉默效应。
