Life Sciences Research Division, Korea Institute of Science and Technology, 39-1 Hawolgok-Dong, Seongbuk-Gu, Seoul, 136-791, Republic of Korea.
Eur J Pharmacol. 2010 Jan 25;626(2-3):123-30. doi: 10.1016/j.ejphar.2009.09.035. Epub 2009 Sep 25.
Low voltage-activated T-type calcium channels are involved in the regulation of the neuronal excitability, and could be subject to many antipsychotic drugs. The effects of clozapine, an atypical antipsychotic drug, on recombinant Ca(v)3.1 T-type calcium channels heterologously expressed in human embryonic kidney 293 cells were examined using whole-cell patch-clamp recordings. At a standard holding potential of -100 mV, clozapine inhibited Ca(v)3.1 currents with an IC(50) value of 23.7+/-1.3 microM in a use-dependent manner. However, 10 microM clozapine inhibited more than 50% of the Ca(v)3.1 currents in recordings at a more physiologically relevant holding potential of -75 mV. Clozapine caused a significant hyperpolarizing shift in the steady-state inactivation curve of the Ca(v)3.1 channels, which is presumably the main mechanism accounting for the inhibition of the Ca(v)3.1 currents. In addition, clozapine slowed Ca(v)3.1 deactivation and inactivation kinetics but not activation kinetics. Clozapine-induced changes in deactivation and inactivation rates of the Ca(v)3.1 channel gating would likely facilitate calcium influx via Ca(v)3.1 T-type calcium channels. Thus, clozapine may exert its therapeutic and/or side effects by altering cell's excitability and firing properties through actions on T-type calcium channels.
低电压激活 T 型钙通道参与神经元兴奋性的调节，可能受到许多抗精神病药物的影响。本文使用全细胞膜片钳记录技术，研究了非典型抗精神病药物氯氮平对人胚肾 293 细胞中表达的重组 Ca(v)3.1 T 型钙通道的作用。在标准的-100 mV 保持电位下，氯氮平以使用依赖性方式抑制 Ca(v)3.1 电流，IC50 值为 23.7+/-1.3 microM。然而，在更接近生理相关的-75 mV 保持电位下的记录中，10 microM 的氯氮平抑制了超过 50%的 Ca(v)3.1 电流。氯氮平引起 Ca(v)3.1 通道稳态失活曲线的显著超极化偏移，这可能是抑制 Ca(v)3.1 电流的主要机制。此外，氯氮平还减慢了 Ca(v)3.1 失活和失活动力学，但不影响激活动力学。氯氮平诱导的 Ca(v)3.1 通道门控失活和失活速率的变化可能会促进钙通过 Ca(v)3.1 T 型钙通道内流。因此，氯氮平可能通过作用于 T 型钙通道来改变细胞的兴奋性和放电特性，从而发挥其治疗和/或副作用。
