MOLECULAR PHYSIOLOGY OF UTERINE SODIUM CHANNELS

电压门控钠通道(NACH)是膜的重要调节器 对神经和肌肉中的动作电位来说是必不可少的。 至少存在两个哺乳动物基因亚家族，第一个亚家族编码 具有良好特征的神经元(脑类型I-III)、心脏和骨骼 肌肉亚型。第二个亚科最近才被发现 并包含一个特征良好的成员(在人类中指定为hNav2.1 和小鼠的mNav2.3)，这可能是最常见的表达在胶质细胞 心脏、子宫和肺中与周围神经相关的细胞。这 处女期和早期子宫肌细胞表面无通道 怀孕的子宫。然而，它在子宫中高水平表达。 妊娠晚期的平滑肌，然后从肌细胞中消失 在交货后几天内浮出水面。此暂态表达式打开 子宫肌细胞表面强烈表明这种蛋白在 在足月子宫收缩中起缺失或允许的作用。这 建议将进一步扩大我们对生理作用的理解 通过1)确定hNav2.1/mNav2.3通道的细胞特异性 胎鼠、成年鼠和人近足月胚胎和成体的蛋白质表达 子宫，2)确定经络的亚基组成 子宫，3)利用异源表达的两种基因研究通道功能 CDNA克隆或子宫肌细胞，以及4)小鼠Nav2.3的特征 吉恩。在继续研究未来基因之前，目标1和4是必要的 转基因小鼠的缺失实验。这些研究工作将 进一步加深我们对蛋白质的理解，这种蛋白质在 子宫收缩能力的调节。通过这项研究获得的知识 将为改进的发展提供必要的背景 调节子宫收缩的药物，了解子宫基因和 妊娠过程中的蛋白质调节及生理学分析 从转基因小鼠中删除Nav2.3基因的后果。在……里面 此外，由于在功能上重要的非典型氨基序列 2.1/2.3通道的区域，这种nach亚型有望极大地 加深对电压门控钠通道结构的认识 函数关系。

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.