MODULATION OF VOLTAGE DEPENDENT POTASSIUM CHANNELS

描述(改编自研究人员的应用)：离子通道 损害了一类特殊的膜蛋白，这些膜蛋白是构成电子的 在神经、肌肉和其他细胞中发出信号。离子通道的调制 特性，特别是通过蛋白质磷酸化的特性是基本的。 对许多细胞类型的功能都很重要。虽然 研究了离子通道的丝氨酸/苏氨酸磷酸化 彻底地，酪氨酸磷酸化对离子通道的调制是 很大程度上是未被开发的。调查者建议检查调制 蛋白酪氨酸激酶与电压门控钾的相互作用 (KV)频道。调查人员将重点调查两名有代表性的成员 Kv通道家族的成员：Dv1.3，它在T淋巴细胞和 一些脑神经元，以及在心脏和脑中高表达的Kv1.5。 这项提议将检验两个假设，每个假设都基于广泛的 初步数据。第一个是一些Kv通道可以紧密关联 与酪氨酸激酶的调节复合体，第二个是有 是Kv通道和酪氨酸激酶的相互调节--也就是， 通道和激酶可以相互调节彼此的活动。这个 研究人员的具体目标是：1)研究分子 Kv通道直接联想的机制和功能后果 和酪氨酸激酶；2)研究其分子机制。 酪氨酸磷酸化调节Kv通道电流；和3) 研究Kv通道和酪氨酸激酶的相互调节。 克隆的Kv1.3和Kv1.5的属性将在它们的 人胚胎肾脏(HEK 293细胞系)中的异源表达 自然Kv通道电流将在培养的嗅球中被研究 神经元。对于这些特定的目标，调查人员将使用 生化、生理和分子方法相结合的方法 剖析调控的分子细节和功能后果 Kv通道与酪氨酸激酶之间的相互作用。

DESCRIPTION (Adapted from the investigator's application): Ion channels compromise a specialized class of membrane proteins that underlie electrical signalling in nerve, muscle and other cells. Modulation of ion channels properties, particularly by protein phosphorylation, is of fundamental importance for the functioning of many cell types. Although serine/threonine phosphorylation of ion channels has been studied thoroughly, modulation of ion channels by tyrosine phosphorylation is largely unexplored. The investigator proposes to examine modulatory interactions between protein tyrosine kinases and voltage-gated potassium (Kv) channels. The investigators will focus on two representative members of the Kv channel family: Dv1.3, which is prominent in T lymphocytes and some brain neurons, and Kv1.5, which is expressed highly in heart and brain. This proposal will test two hypotheses, each of which is based on extensive preliminary data. The first is that some Kv channels can associate tightly with tyrosine kinases in a regulatory complex, and the second is that there is reciprocal regulation of Kv channels and tyrosine kinases - that is, channels and kinases can regulate each other's activities. The investigator's specific aims are: 1) To investigate the molecular mechanisms and functional consequences of direct association of Kv channels and tyrosine kinases; 2) to investigate the molecular mechanisms by which tyrosine phosphorylation modulates Kv channels current; and 3) to investigate the reciprocal regulation of Kv channels and tyrosine kinsases. The properties of cloned Kv1.3 and Kv1.5 will be examined following their heterologous expression in a human embryonic kidney (HEK 293 cell line, and native Kv channel current will be investigated in cultured olfactory bulb neurons. For each of these specific aims, the investigators will use a combination of biochemical, physiological and molecular approaches to dissect the molecular details and functional consequences of modulatory interactions between Kv channels and tyrosine kinases.