Cellular Regulation of Salt Taste Transduction

描述(申请人提供)：盐味在NaCI和其他矿物盐的检测中起着至关重要的作用，是维持离子和水平衡的多器官调节系统的一部分。了解盐味感受器的性质及其调节对于临床治疗与过量盐摄入有关的疾病具有重要意义。有两种类型的盐味感受器，一种是钠离子特有的，另一种是不区分钠、钾和氨离子的。心尖部对阿米洛利敏感的上皮性钠通道构成了钠盐味觉受体。一个重要但只有部分答案的问题是：第二个非特异性阳离子受体的分子和生化特性是什么？这项建议的一个主要目的是鉴定这一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探针：氯化十六烷基吡啶，它依赖于其浓度，既是这一途径的激动剂，也是其拮抗剂，这表明该受体是一种非特异性的阳离子通道。我们建议通过电生理学、药理学和分子方法进一步表征这一途径。如果这个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受体通道的特性。我们在认识上存在重大差距的其他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。我们将利用鼓索和舌咽味觉神经记录，在电压钳下记录舌部感受野。这些研究将通过测量在电压钳条件下保留上皮组织极性的完整菌状和环状乳头中细胞内钠、钾、钙和pH的变化来补充。鉴定调节非特异性阳离子受体通道的类似于十六烷基氯化吡啶的天然和合成类似物可能作为盐味增强剂或抑制剂具有潜在的实用价值。

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.