MOLECULAR PHYSIOLOGY OF UTERINE SODIUM CHANNELS

电压门控钠通道（NaCh）是细胞膜的重要调节剂， 是神经和肌肉动作电位的基础。 至少存在两个哺乳动物基因亚家族，其中第一个编码 充分表征的神经元（脑I-III型）、心脏和骨骼 肌肉亚型第二个亚科最近才被发现 并含有一个充分表征的成员（在人类中命名为hNav2.1 和小鼠中的mNav2.3），其可能最常在神经胶质细胞中表达。 与心脏、子宫和肺中的外周神经相关的细胞。这 通道是缺乏从子宫肌细胞表面在处女和早期 妊娠子宫然而，它在子宫内膜中以高水平表达， 在妊娠晚期平滑肌，然后从肌细胞中消失 交货后几天内浮出水面。这个短暂的表达 子宫肌细胞表面强烈表明这种蛋白质在子宫内膜中起着重要作用， 在足月子宫收缩中起着间接或间接的作用。这 该提案将进一步扩大我们对生理作用的理解， hNav2.1/mNav2.3通道的细胞特异性， 在胎儿和成年小鼠以及人类近期的蛋白表达 子宫，2）确定长期通道的亚基组成 子宫，3）使用异源表达的 cDNA克隆或子宫肌细胞，和4）表征小鼠Nav2.3 基因目标1和目标4是在进行未来基因之前必须的 在转基因小鼠中的缺失实验。这些研究工作将 进一步加深了我们对蛋白质的理解， 调节子宫收缩力。通过本研究获得的知识 将提供必要的背景，为发展改善 调节子宫收缩的药物，了解子宫基因， 妊娠期蛋白质的调节，并分析其生理 从转基因小鼠中删除Nav2.3基因的后果。在 此外，由于非典型氨基酸序列在功能上重要， 在2.1/2.3通道的区域，这种NaCh同种型有望大大提高 增加我们对电压门控钠通道结构理解 功能关系。

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.