MOLECULAR PHYSIOLOGY OF UTERINE SODIUM CHANNELS

子宫钠通道的分子生理学

• 批准号: 2403551
• 负责人: Michael M. TAMKUN
• 金额: $ 16.89万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2403551
• 关键词: Xenopus oocyte; birth; blocking antibody; developmental genetics; embryo /fetus cell /tissue; female; gene expression; genetic library; genetic promoter element; human pregnant subject; human tissue; in situ hybridization; laboratory mouse; laboratory rabbit; messenger RNA; muscle cells; muscle contraction; myometrium; nucleic acid sequence; posttranscriptional RNA processing; protein isoforms; protein structure function; sodium channel; voltage /patch clamp; voltage gated channel

Voltage-gated sodium channels (NaCh) are important modulators of membrane potential and are essential for the action potential in nerve and muscle. At least two mammalian gene subfamilies exist, the first of which encodes the well characterized neuronal (brain types I-III), cardiac, and skeletal muscle isoforms. The second subfamily has only recently been discovered and contains one well characterized member (designated hNav2.1 in human and mNav2.3 in mouse) that is probably most commonly expressed in glial cells associated with peripheral nerve in heart, uterus, and lung. This channel is absent from the uterine myocyte surface in virgin and early pregnancy uterus. However, it is expressed at high levels in uterine smooth muscle at late pregnancy and then disappears from the myocyte cell surface within several days after delivery. This transient expression on the uterine myocyte surface strongly suggests that this protein plays either a delect or permissive role in uterine contraction at term. This proposal will further expand our understanding of the physiological role of the hNav2.1/mNav2.3 channels by 1) determining the cell specificity of protein expression in the fetal and adult mouse and human near term uterus, 2) determining the subunit composition of the channel in term uterus, 3) studying channel function using either heterologously expressed cDNA clones or uterine myocytes, and 4) characterizing the mouse Nav2.3 gene. Goals 1 and 4 are necessary prior to proceeding with a future gene deletion experiment in a transgenic mouse. These research efforts will further our understanding of a protein which is important in the regulation of uterine contractility. Knowledge gained through this study will provide the necessary background for the development of improved drugs for regulating uterine contraction, understanding uterine gene and protein regulation during pregnancy, and analysis of the physiological consequences of deleting the Nav2.3 gene from a transgenic mouse. In addition, due to the atypical amino sequence in functionally important regions of the 2.1/2.3 channels, this NaCh isoform promises to greatly increase our understanding of voltage-gated sodium channel structure function relationships.

电压门控钠通道（NACH）是膜的重要调节剂 潜力，对于神经和肌肉的动作潜力至关重要。 至少存在两个哺乳动物基因亚科，第一个编码 良好特征的神经元（脑类I-III），心脏和骨骼 肌肉同工型。第二个亚科直到最近才发现 并包含一个特征良好的成员（人类指定的HNAV2.1 和mnav2.3在鼠标中）可能最常见于胶质 与心脏，子宫和肺部周围神经有关的细胞。这 在处女中的子宫肌细胞表面不存在通道 怀孕子宫。但是，它在子宫中以高水平表示 怀孕晚期的平滑肌，然后从心肌细胞中消失 交付后几天内表面表面。这种瞬态表达在 子宫肌细胞表面强烈表明该蛋白质发挥作用 在学期中，在子宫收缩中的妄想或允许作用。这 建议将进一步扩大我们对生理角色的理解 通过1）确定细胞特异性 胎儿和成年小鼠和人类的蛋白质表达 子宫，2）确定通道的亚基组成 子宫，3）使用两种异源表达的通道功能 cDNA克隆或子宫肌细胞，4）表征鼠标NAV2.3 基因。目标1和4是在进行未来基因之前必要的 转基因小鼠中的缺失实验。这些研究工作将 进一步我们对蛋白质的理解在 子宫收缩性的调节。通过这项研究获得的知识 将为开发改进提供必要的背景 用于调节子宫收缩的药物，了解子宫基因和 怀孕期间的蛋白质调节和生理学分析 从转基因小鼠中删除NAV2.3基因的后果。在 此外，由于功能上重要的非典型氨基序列 2.1/2.3频道的区域，该NACH同工型承诺将极大地 增加我们对电压门控钠通道结构的理解 功能关系。