FUNCTION & REGULATION OF GASTRIC NA/K/2CL COTRANSPORTERS

功能

• 批准号: 6045482
• 负责人: CHRISTIAN Y LYTLE
• 金额: $ 16.83万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6045482
• 关键词: cell migration; chloride ion; gastric juice; gastric mucosa; gastrointestinal absorption /transport; hydrochloric acid; hydrogen potassium exchanging ATPase; laboratory rabbit; laboratory rat; membrane transport proteins; microspectrophotometry; potassium ion; protein localization; protein structure function; secretion; sodium ion

The gastric mucosa secretes digestive hydrochloric acid and pepsin in coordination with dietary intake. Although it is now axiomatic that parietal cells secrete HCl, a growing body of evidence indicates that these cells undergo major morphological, biochemical, and functional changes as they migrate down into the neck and base of the gastric gland. The nature and functional significance of these changes are poorly understood. We show that parietal cell transformation includes a sudden and prodigious expression of the secretory Na-K-2Cl cotransporter (NKCC). The migration-associated expression of NKCC is topologically correlated with loses of Cl/HCO3 exchanger (AE2) and H,K-ATPase activity, and with expression of aquaporin-4 water channels. We hypothesize that downwardly-migrating parietal cells might undergo a programmed conversion of their principal function from acidic chloride (HCl) secretion to nonacidic chloride (NaCl) secretion. The secretion of a saline fluid volume by parietal cells in the base of the gland might serve to flush the lumen of local pepsinogen and distal acid. The project proposed here consists of four complementary studies. Aim 1 will determine the functional consequences of NKCC expression and AE2 loss during parietal cell migration on intracellular Cl- homeostasis and vectorial Cl- transport by microspectrofluorometric imaging of isolated gastric glands. Aim 2 will begin to delineate the signals, receptors, and intracellular mediators that regulate NKCC in basilar parietal cells in vitro and in vivo. Aim 3 will directly test whether parietal cells in the gland base cease to function as robust acid secretors, as previous evidence has suggested. Finally, Aim 4 will map the cellular and subcellular distribution of K-Cl cotransporter-1 (KCC1) in gastric mucosa and begin to assess the possibility that K-Cl cotransporter-1 (KCC1) may contribute to apical K+ recycling in parietal cells. Completion of these aims will begin to clarify the functional consequences of the migration-associated differentiation of parietal cells.

胃粘膜分泌消化盐酸和胃蛋白酶与饮食摄入协调。 尽管现在的天壁细胞分泌HCl是公理的，但越来越多的证据表明，这些细胞在迁移到胃腺的颈部和底部时会发生主要的形态，生化和功能变化。 这些变化的性质和功能意义知之甚少。 我们表明，顶点细胞的转化包括分泌Na-K-2Cl共转运蛋白（NKCC）的突然表达。 NKCC的迁移相关表达与Cl/HCO3交换器（AE2）和H，K-ATPase活性的损失以及Aquaporin-4水通道的表达相关。 我们假设向下迁移的顶叶细胞可能会经历其主要功能从酸性氯化物（HCL）分泌到非氯化物（NACL）分泌的编程转换。 腺体底部的顶细胞分泌盐水液体积可能会冲洗局部百事可乐和远端酸的腔。 这里提出的项目由四项互补研究组成。 AIM 1将确定在细胞内CL-稳态上NKCC表达和AE2损失的功能后果，以及通过微光谱荧光计量学成像分离的胃腺对矢量cl-转运的功能后果。 AIM 2将开始描绘体外和体内基底壁细胞中NKCC的信号，受体和细胞内介质。 正如先前证据所表明的那样，AIM 3将直接测试腺体碱基中的顶细胞是否停止起到稳健的酸性损伤作用。 最后，AIM 4将绘制胃粘膜中K-CL共转运蛋白-1（KCC1）的细胞和亚细胞分布，并开始评估K-CL cotransporter-1（KCC1）可能有助于顶层细胞中的顶端K+再生循环弹出的可能性。 这些目的的完成将开始阐明顶细胞与迁移相关的分​​化的功能后果。