Properties of Ion Channels that Control Secretion

控制分泌的离子通道的特性

基本信息

批准号：
7474727
负责人：
JOHN J ENYEART
金额：
$ 26.12万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-13 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7474727
关键词：
ATP Hydrolysis Action Potentials Addison&apos s disease Adrenal Cortex Adrenal Cortex Hormones Adrenal Glands Aldosterone Angiotensin II Blood Glucose Blood Pressure Bos taurus Brain Brain Injuries Calcium Cattle Cells Cessation of life Code Corticotropin Coupled Coupling Cyclic AMP Electrolytes Endocrine Energy-Generating Resources Equilibrium Event Gene Expression Generations Glucocorticoids Glucose Glucose Plasma Concentration Hormonal Hormones Hydrocortisone Hydrolysis Hypoglycemia In Situ Hybridization Ion Channel Link Mammals Mediating Membrane Membrane Potentials Metabolic Mineralocorticoids Modeling Molecular Molecular Cloning Northern Blotting Pathology Pathway interactions Peptides Peripheral Phosphotransferases Physiological Pituitary Gland Plasma Potassium Channel Production Property Range Receptor Activation Regulation Role Signal Pathway Signal Transduction Stimulus Testing Water Zona Fasciculata Zona Glomerulosa electrical property energy balance paracrine patch clamp potassium channel protein TREK-1 research study response sensor sugar voltage

项目摘要

DESCRIPTION (provided by applicant): The adrenal cortex of mammals is divided into an outer glomerulosa and inner fasciculata that secrete different corticosteroid hormones, including the mineralocorticoid aldosterone and the glucocorticoid cortisol. These hormones function critically in regulating electrolyte, water, and energy balance, and are therefore vital for maintaining blood pressure and plasma glucose within normal limits. Precise control of blood glucose by cortisol is essential because this sugar is the brain's primary energy source. Hypoglycemia rapidly leads to brain damage and death. Aberrant secretion of corticosteroids causes endocrine pathology, including Cushing's and Addison's diseases. At the cellular level, cortisol secretion by adrenal zona fasciculata (AZF) cells is controlled primarily by the pituitary peptide ACTH, while zona glomerulosa (AZG) cells secrete aldosterone in response to the peripheral peptide Angiotensin II (All). Although many of the physiological stimuli and intracellular messengers that regulate secretion of corticosteroids have been identified, the signaling pathways that link these stimuli to secretion are incompletely understood. In particular, the role of electrical activity and specific ion channels in the secretion of corticosteroids has not been clarified. Bovine AZF and AZG cells express several ion channels that determine their electrical properties and the ionic events involved in secretion. The K+ channel bTREK-1 sets the resting potential, is activated by ATP and inhibited by ACTH and All. Thus, TREK-1 channels act pivotally in integrating hormonal and metabolic signals and coupling these to depolarization-dependent calcium (Ca2+) entry and secretion. A specific model has been developed for ACTH- and All-stimulated cortisol and aldosterone secretion that depends on the generation of Ca2+-dependent action potentials. Specifically, the inhibition of bTREK-1 K+ channels by ACTH and All leads to action potentials driven by opposing voltage-gated Ca2+ and K+ currents. Experiments described in this proposal test this hypothesis and identify signaling pathways that control function and expression of adrenocortical ion channels. Specific Aims will be: 1) To demonstrate that All inhibits bTREK-1 K+ channels in bovine AZF and AZG cells by separate Ca2+ - and ATP hydrolysis-dependent signaling pathways, and to identify their molecular mechanisms. To demonstrate that bTREK-1 channels set the resting potential of bovine AZG cells and that inhibition of these channels by All is coupled to depolarization-dependent aldosterone secretion; 2) To demonstrate that ACTH exerts short and long term control over the electrical properties of bovine AZF cells by regulating both the function and expression of AZF cell ion channels and to characterize the molecular mechanisms involved; and 3) To determine whether the ATP sensitivity of native bTREK-1 channels allows them to function as sensors whose activity varies with the plasma glucose concentration and the metabolic state of the AZF cell.

描述（由申请人提供）：哺乳动物的肾上腺皮质被分为外肾小球和内部fasciculata，分泌不同的皮质类固醇激素，包括盐皮质激素醛固酮和糖皮质激素皮质醇。这些激素对调节电解质，水和能量平衡的关键作用，因此对于在正常极限内保持血压和血浆葡萄糖至关重要。皮质醇对血糖的精确控制是必不可少的，因为该糖是大脑的主要能源。低血糖迅速导致脑损伤和死亡。皮质类固醇的异常分泌会导致内分泌病理学，包括Cushing和Addison的疾病。在细胞水平上，肾上腺Zona fasciculata（AZF）细胞的皮质醇分泌主要由垂体肽ACTH控制，而Zona glomerulosa（AZG）细胞分泌醛固酮，响应外围肽血管素II（ALL）。尽管已经确定了调节皮质类固醇分泌的许多生理刺激和细胞内信使，但将这些刺激与分泌的信号传导途径尚不完全理解。特别是，尚未阐明电活动和特定离子通道在皮质类固醇分泌中的作用。牛AZF和AZG细胞表达了几个离子通道，这些离子通道确定其电特性和分泌所涉及的离子事件。 K+通道BTREK-1设置了静息电位，被ATP激活，并被ACTH和ALL抑制。因此，TREK-1通道在整合激素和代谢信号并将其与去极化依赖性钙（CA2+）进入和分泌方面偶性地作用。已经为ACTH和全刺激的皮质醇和醛固酮分泌开发了一个特定的模型，该模型取决于Ca2+依赖性作用电位的产生。具体而言，ACTH对BTREK-1 K+通道的抑制以及所有导致反对电压门控CA2+和K+电流驱动的动作电位。本提案中描述的实验检验了该假设并确定控制肾上腺皮质离子通道功能和表达的信号通路。具体目的是：1）证明所有人都通过单独的Ca2+ - 和ATP水解依赖性信号通路抑制牛AZF和AZG细胞中的Btrek-1 K+通道，并鉴定其分子机制。为了证明BTREK-1通道设定了牛AZG细胞的静息潜力，并且抑制这些通道的抑制作用与去极化依赖性醛固酮分泌耦合； 2）证明ACTH通过调节AZF细胞离子通道的功能和表达并表征所涉及的分子机制，从而对牛AZF细胞的电性能进行短期和长期控制； 3）确定天然BTREK-1通道的ATP敏感性是否使它们充当传感器，其活性随血浆葡萄糖浓度和AZF细胞的代谢状态而变化。