STRUCTURE/FUNCTION ANALYSIS OF VOLTAGE-GATED CA CHANNELS

电压门控钙通道控制钙离子进入细胞 生理和病理条件。他们是一个大班的目标 在控制高血压的药物中，它们是自身免疫的靶点 导致细胞死亡的反应，如在罕见疾病中可能发生的反应 肌萎缩侧索硬化症以及更常见的疾病，如 为I型糖尿病。对它们的多样性、复杂性的理解 而它们的运作是至关重要的。 研究的目的是将字母1的结构要素联系起来 和钙通道的β亚基对其功能特性的影响。这个 使用的基本工具是通过重组DNA构建 突变型和嵌合型分子及其检测技术 在非洲爪哇卵母细胞中的相互作用和表达特性。 预期积极的信息将通过这些 操控是基于1.通过分子克隆获得 在我们的两个同源的Alpha1cDNAs中，C型和E型具有 区分电生理和药理学特性和 可在非洲爪哇卵母细胞中良好表达；2.通过 几种β亚基基因我们部分的分子克隆 也在非洲爪哇的卵母细胞中表达，其中一些传递 共表达时区分α1亚基的特性 非洲爪哇卵母细胞；3.通过猪的协作进行的联合 与Enrico Stefani博士一起，他将进行彻底和有洞察力的 构建的人工血管的电生理特性分析 分子。 特定的目标集中在通过构建嵌合体来阐明 Alpha1的主要结构-功能关系，试图 确定某些钙失活所需的结构，但不是 其他，用于电压失活，用于通过磷酸化和 关键的药理作用。 申请作为调查员发起的申请的一部分提交 研究项目补助金(IRPG)。同伴助学金是斯蒂芬尼博士喜欢的类型 II续期申请AR-38970。这些研究的结果可能 有助于设计更好的治疗剂。

Voltage grated Ca2+ channels control entry of Ca2+ into cells under physiologic and pathologic conditions. They are targets of a major class of hypertension controlling drugs, they are targets of autoimmune reactions that lead to cell death as may happen in rare diseases such as amyotrophic lateral sclerosis as well as in more frequent diseases such as type I diabetes. An understanding of their diversity, their complexity and their functioning is of central importance. The aim of the research is to relate structural elements of the alpha1 and beta subunits of Ca2+ channels to their functional properties. The basic tools to be used are the construction via recombinant DNA techniques of mutant and chimeric molecules and the measurement of their interaction and properties upon expression in Xenopus oocytes. The expectation that positive information will be obtained through these manipulations is based on 1. the acquisition through molecular cloning on our part of two homologous alpha1 cDNA's, type C and type E, that have distinguishing electrophysiological and pharmacological properties and can be expressed well in Xenopus oocytes; 2. the acquisition through molecular cloning on our part of several beta subunit cDNA's that can also be expressed in Xenopus oocytes and of which some impart distinguishing properties to the alpha1 subunits when co-expressed in Xenopus oocytes; and 3. the association through collaboration of the PI with Dr. Enrico Stefani, who will carry out a thorough and insightful analysis of the electrophysiological properties of the constructed molecules. Specific aims center on the elucidation through construction of chimeras of the major structure-function relations for alpha1 in an attempt to determine those structures required for Ca2+ inactivation of some but not others, for voltage inactivation, for regulation by phosphorylation and for key pharmacologic properties. The application is submitted as part of an Investigator-initiated Research Project Grant (IRPG). The companion grant is Dr. Stefani's type II renewal application AR-38970. Results from these studies may contribute to the design of better therapeutic agents.