Cellular Regulation of Salt Taste Transduction

描述（由申请人提供）：盐味在检测NaCI和其他矿物盐中起着至关重要的作用，是维持离子和水稳态的多器官调节系统的一部分。了解盐味受体的性质及其调控对过量盐摄入相关疾病的临床治疗具有重要意义。有两种类型的盐味觉受体，一种是钠特异性的，另一种不区分钠、钾和铵离子。顶端对阿米洛利钠敏感的上皮钠通道构成钠特异性盐味受体。一个重要的但只是部分回答的问题是：第二种非特异性阳离子受体的分子和生化特性是什么？本提案的主要目的是鉴定该受体通道的天然和合成激动剂和拮抗剂，以揭示其生化特性。我们最近发现了一种药理学探针；十六烷基吡啶氯化，取决于其浓度作为这一途径的激动剂和拮抗剂，这表明受体是一个非特异性阳离子通道。我们建议通过电生理、药理学和分子方法进一步表征这一途径。如果这种受体通道存在于其他组织中，我们将比较味觉受体细胞和已知表达它的组织中的受体通道的特性。我们在理解上存在重大差距的另一个重要领域是涉及盐味调节的机制。因此，我们将研究cAMP、pH、钙和温度的变化如何调节这两个受体通道。我们将在电压钳下利用舌感受野记录鼓室索和舌咽部味觉神经。这些研究将通过测量在电压钳条件下保存上皮组织极性的完整的真菌状和环形乳头中细胞内钠、钾、钙和pH活性的变化来补充。天然和合成的类似十六烷基吡啶氯调节非特异性阳离子受体通道的类似物可能是潜在的有用的盐味增强剂或抑制剂。

DESCRIPTION (provided by applicant): Salt taste plays an essential role in the detection of NaCI and other mineral salts and is part of the multi-organ regulatory system that maintains ion and water homeostasis. Understanding the nature of salt taste receptors and their regulation is important in the clinical management of diseases related to excess salt intake. There are two types of salt taste receptors, one that is sodium-specific and a second that does not discriminate among sodium, potassium, and ammonium ions. The apical amiloride-sensitive epithelial sodium channels constitute the sodium-specific salt taste receptor. One important and yet only partially answered question is: what is the molecular and biochemical identity of the second non-specific cation receptor? A major aim of this proposal is to identify natural and synthetic agonists and antagonists of this receptor channel that will reveal its biochemical identity. We have recently identified a pharmacological probe; cetylpyridinium chloride that depending upon its concentration acts as both an agonist and antagonist of this pathway and which suggests the receptor is a non-specific cation channel. We propose to characterize this pathway further by electrophysiological, pharmacological, and molecular methods. If this receptor channel is present in other tissues we will compare the properties of the receptor channel in taste receptor cells and in a tissue known to express it. Additional important areas in which we have significant gaps in our understanding are the mechanisms involved in the regulation of salt taste. Accordingly we will investigate how changes in cAMP, pH, calcium, and temperature regulate these two receptor-channels. We will utilize chorda tympani and glossopharyngeal taste nerve recordings with the lingual receptive field under voltage-clamp. These studies will be complemented by measuring changes in intracellular sodium, potassium, calcium, and pH activities in intact fungiform and circumvaliate papillae with epithelial tissue polarity preserved under voltage-clamp conditions. The identification of natural and synthetic analogues similar to cetylpyridinium chloride that modulate the non-specific cation receptor channel may be potentially useful as salt taste enhancers or suppressers.