CHARACTERIZATION OF ANTIARRHYTHMIC DRUG BINDING SITES IN VOLTAGE GATED CHANNELS

电压门控通道不仅对无数的生理功能至关重要， 在心脏中起作用，但也作为各种分子靶点， 抗肿瘤剂。 随着最近的克隆，测序， 表达的电压门控钠和钾通道，阶段现在设置为 确定主要参与抗- 对电压门控Na和K通道的药理作用。 特别是， 野生型和突变型的电压门控Na通道衍生 来自成人骨骼肌（mu1，Trimmer等，1990年，A 来源于人心脏的电压门控K通道（HK1，或Kv1.4，Tamkun 例如，1991）将在哺乳动物细胞系中表达，并通过 膜片钳方法检测功能变化的影响， 内部应用QX-314（用于mu1）和氯非铵（用于HK1），永久性 带电的抗肿瘤剂 基因突变将会 根据最近的工作定位可能的行动地点， 内部活性抗肿瘤剂的细胞质前庭 Na和K通道（Gingrich等人，1993; Backx等人，1992年，Choi et 例如，1993年）。 揭示重要的氨基酸排列 毒品行动将是一个关键的先决条件，以解开 在分子水平上的抗肿瘤作用机制。 等 理解在合理的药物治疗和设计中将是无价的。

Voltage-gated channels are not only essential to countless physiological functions in heart, but also serve as the molecular target of diverse anti-arrhythmic agents. With the recent cloning, sequencing, and expression of voltage-gated Na and K channels, the stage is now set to identify the key amino acid residues primarily involved in anti- arrhythmic action on voltage-gated Na and K channels. In particular, wild-type and mutant versions of both a voltage-gated Na channel derived from adult skeletal muscle (mu1, Trimmer et al., 1990), as well as a voltage-gated K channel derived from human heart (HK1, or Kv1.4, Tamkun et al., 1991) will be expressed in a mammalian cell line and probed by patch-clamp methods to detect functional changes in the effects of internally applied QX-314 (for mu1) and clofilium (for HK1), permanently charged versions of anti-arrhythmic agents. Mutations will be made according to recent work localizing the probable site of action of internally active anti-arrhythmic agents to the cytoplasmic vestibule of Na and K channels (Gingrich et al., 1993; Backx et al., 1992, Choi et al., 1993). Unmasking the arrangement of amino acids that are important for drug action would be a crucial prerequisite to unravelling the mechanism of anti-arrhythmic action at the molecular level. Such understanding would be invaluable in rational drug therapy and design.