Nelson M T, Todorovic S M, Perez-Reyes E
Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA.
Curr Pharm Des. 2006;12(18):2189-97. doi: 10.2174/138161206777585184.
T-type calcium channels open in response to small depolarizations of the plasma membrane. The entry of two positive charges with every calcium ion leads to a further depolarization of the membrane, the low threshold spike, and opening of channels that have a higher threshold. In this manner, T-channels play an important pacemaker role in gating the activity of Na+ and Ca2+ channels. T-channels are preferentially expressed in dendrites, suggesting they play important roles in synaptic integration. Pharmacological evidence indicates that they are expressed in the receptive fields of sensory neurons, suggesting they play a primary role in nociception. Molecular cloning of the three T-channel genes has allowed detailed studies on their channel properties, pharmacology, distribution in the brain, up-regulation in animal models of disease, and provided the tools to screen for novel drugs. Studies on transgenic animals have provided the proof-of-concept that T-channels are important drug targets for the treatment of absence epilepsy and neuropathic pain. Mutations in ion channel genes, or channelopathies, have been found in many diseases. Similarly, T-channel gene mutations have been found in patients with childhood absence epilepsy. Considering the important role T-channels play in the thalamus, it is likely that T-channel mutations also contribute to a wider range of disorders characterized by thalamocortical dysrhythmia.
T型钙通道会因质膜的小去极化而开放。每个钙离子携带两个正电荷进入细胞会导致膜进一步去极化，即产生低阈值尖峰，并使阈值较高的通道开放。通过这种方式，T型通道在调控Na+和Ca2+通道的活性方面发挥着重要的起搏作用。T型通道在树突中优先表达，这表明它们在突触整合中发挥重要作用。药理学证据表明它们在感觉神经元的感受野中表达，这表明它们在伤害感受中起主要作用。对三个T型通道基因的分子克隆使得对其通道特性、药理学、在大脑中的分布、疾病动物模型中的上调情况进行详细研究成为可能，并提供了筛选新药的工具。对转基因动物的研究提供了概念验证，即T型通道是治疗失神癫痫和神经性疼痛的重要药物靶点。在许多疾病中都发现了离子通道基因突变，即通道病。同样，在儿童失神癫痫患者中也发现了T型通道基因突变。考虑到T型通道在丘脑中的重要作用，T型通道突变很可能也导致了以丘脑皮质节律紊乱为特征的更广泛的疾病。
