The Physiological Roles of K Channels in Fluid Secretion

K 通道在液体分泌中的生理作用

• 批准号: 7190564
• 负责人: TED B BEGENISICH
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7190564
• 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; Condition; Data; Dependence; Duct (organ) structure; Eating; Electrolytes; Electrophysiology (science); Epicholesterol; Epithelium; Equilibrium; Event; Financial compensation; Fluids and Secretions; Functional disorder; Genes; Goals; Health; Human; Image; In Situ; Ion Channel; Knockout Mice; Lead; Leucine Zippers; Liquid Chromatography; Liquid substance; Localized; 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; Personal Satisfaction; Physiological; Physiology; Population; Potassium; Potassium Channel; Proteins; Research Personnel; Role; Saliva; Salivary; Salivary Glands; Signal Transduction; System; Techniques; Testing; apical membrane; caveolin 1; design; driving force; human tissue; large-conductance calcium-activated potassium channels; mouse model; novel; patch clamp; programs; research study; saliva composition; saliva secretion; tandem mass spectrometry; uptake; voltage

DESCRIPTION (provided by applicant): 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-activated K 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 posited 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 channel genes.

描述（由申请人提供）：数百万美国人患有唾液腺功能障碍。唾液分泌对于说话、进食和维持口腔健康是必需的，并且不能产生足够的唾液分泌会导致多种病症，这些病症共同构成了很大一部分人口的主要健康问题。液体分泌上皮利用离子通道和运输机制的复杂相互作用。持续的液体分泌需要交感神经刺激唾液腺腺泡细胞上的毒蕈碱受体产生细胞内钙的增加。细胞内钙的增加会激活钙敏感的钾 (K) 和阴离子通道，共同驱动液体分泌。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 的候选基因。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未知。使这个问题变得复杂的是初步的新发现，即 IK1 通道的激活会抑制 maxi-K 通道电流。该项目的长期目标是确定这两类 K 通道的生理作用。实现这一目标需要确认 maxi-K 基因的身份并确定它们之间相互作用的机制。假设这两个通道与其他蛋白质共定位于腮腺腺泡细胞中，并直接或通过紧密相连的中介相互作用，并且可能具有不同的钙和/或毒蕈碱敏感性。将测量这两个通道的钙和毒蕈碱敏感性并结合膜片钳电生理学、光学、生物化学和分子生物学技术测试了它们的相互作用机制。将通过对两个 K 通道基因表达缺陷的小鼠进行各种生理测量来探讨这两个通道的生理作用。