The Physiological Roles of K Channels in Fluid Secretion

K 通道在液体分泌中的生理作用

基本信息

批准号：
7777852
负责人：
TED B BEGENISICH
金额：
$ 35.22万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777852
关键词：
Acinar Cell Agonist American Animals Anions Apoptosis Biochemical Biological Calcium Calcium-Activated Potassium Channel Candidate Disease Gene Caveolins Cell membrane Cells Cholesterol Code Complex Data Dependence Duct (organ) structure Eating Electrolytes Electrophysiology (science)Epicholesterol Epithelium Equilibrium Event Financial compensation Fluids and Secretions Functional disorder Genes Goals Health Human In Situ Ion Channel Knockout Mice Lead Leucine Zippers Liquid Chromatography Liquid substance Measurement Measures Membrane Membrane Lipids Membrane Potentials Methods Molecular Molecular Genetics Mus Muscarinic Acetylcholine Receptor Muscarinic Agonists Muscarinics Names Nerve Optics Oral health Parotid Gland Physiological Physiology Population Potassium Potassium Channel Proteins Research Personnel Role Saliva Salivary Salivary Glands Signal Transduction System Techniques Testing apical membrane design driving force human tissue imaging modality large-conductance calcium-activated potassium channels mouse model novel patch clamp programs protein complex research study saliva composition tandem mass spectrometry uptake voltage

项目摘要

Millions of Americans suffer from salivary gland dysfunction. Salivary fluid secretion is necessary for speaking, eating, and for maintaining oral health and the inability to produce adequate salivary fluid secretion results in a variety of conditions that together comprise a major health problem for a significant proportion of the population. Fluid secreting epithelia utilize a complex interplay of ion channels and transport mechanisms. Sustained fluid secretion requires an increase in intracellular calcium produced by sympathetic nerve stimulation of muscarinic receptors on salivary gland acinar cells. This increase in intracellular calcium activates calcium-sensitive potassium (K) and anion channels which, together, drive fluid secretion. Salivary glands contain two types of calcium-activatedK channels named IK1 and maxi-K. The gene encoding the IK1 channel (Kcnn4) has been identified and Kcnmal is a candidate gene for maxi- K. In spite of considerable effort, the specific roles for these two channels in salivary glands remain unknown. Complicating this issue is the preliminary, novel finding that the activation of IK1 channels inhibits maxi-K channel current. The long term goal of this project is to determine the physiological roles for these two types of K channels. Achieving this goal will require confirming the identity of the maxi-K gene and determining the mechanism of the interaction between them. It is hypothesized that these two channels are co-localized in parotid acinar cells with other proteins and interact directly or through a closely-apposed intermediary and may have different calcium and/or muscarinic sensitivities The calcium and muscarinic sensitivities of these two channels will be measured and their mechanism of interaction tested with a combination of patch clamp electrophysiology, optical, biochemical, and molecular biological techniques. The physiological roles of the two channels will be probed with various physiological measurements of mice deficient in the expression of the two K channelgenes.

数百万美国人患有唾液腺功能障碍。唾液分泌是必需的说话、吃饭和维持口腔健康以及无法产生足够的唾液分泌导致多种状况，这些状况共同构成了很大一部分人的主要健康问题人口。液体分泌上皮利用离子通道和运输的复杂相互作用机制。持续的液体分泌需要细胞内钙的增加交感神经刺激唾液腺腺泡细胞上的毒蕈碱受体。这一增加细胞内钙激活钙敏感性钾 (K) 和阴离子通道，它们共同驱动体液分泌。唾液腺含有两种钙激活 K 通道，称为 IK1 和 maxi-K。编码 IK1 通道 (Kcnn4) 的基因已被鉴定，Kcnmal 是 maxi- K. 尽管付出了相当大的努力，这两个通道在唾液腺中的具体作用仍然存在未知。使这个问题复杂化的是初步的新发现，即 IK1 通道的激活会抑制最大 K 通道电流。该项目的长期目标是确定这些的生理作用两种类型的 K 通道。实现这一目标需要确认 maxi-K 基因的身份以及确定它们之间相互作用的机制。假设这两个通道是与其他蛋白质共定位于腮腺腺泡细胞中，并直接或通过紧密贴合的蛋白质相互作用中间，可能有不同的钙和/或毒蕈碱敏感性钙和毒蕈碱将测量这两个通道的敏感性并用膜片钳电生理学、光学、生物化学和分子生物学技术的结合。将通过小鼠的各种生理测量来探讨这两个通道的生理作用两个 K 通道基因的表达存在缺陷。