L-amino and acid taste in mice.

描述(由申请人提供)： 主要的味觉(甜、酸、苦、盐和鲜味)通常与不同类型的食物有关。例如，鲜味通常是食物富含蛋白质和某些L氨基酸的信号。然而，这些感觉的基础是有争议的，也没有被很好地理解。分子和有限的行为学研究已经确定了一种候选味觉受体，T1R1/T1R3，它可以检测包括谷氨酸钠在内的鲜味刺激，以及更多的L氨基酸。相反，其他分子和行为学研究报告有证据表明，L-AP4(一种强有力的mGluR4激动剂)可以诱发模拟手指刺激的传入信号，这表明味觉-mGluR4受体参与了鲜味。对缺乏T1R3的小鼠进行的研究加剧了这一争议。一项研究报告称，T1R3基因敲除小鼠完全消除了鲜味(赵等人，2003年)，而另一项独立开发的T1R3基因敲除小鼠的研究报告仅减少了鲜味(Damak等人，2003年)。使用从Damak等人获得的T1R3基因敲除小鼠进行的试点阈值实验。研究发现，这些小鼠可以品尝到味精，几乎和遗传背景相同的野生型小鼠一样。此外，对大鼠的初步研究表明，mGluR4拮抗剂改变了L-谷氨酸的味道，但对氨基酸L-精氨酸的味道几乎没有影响。这些数据和其他研究表明，T1R3以外的受体对鲜味有贡献。 这项提议中的两个特定目标将检验这样的假设，即一些L氨基酸(例如L-谷氨酸)由两个受体(T1R1/T1R3，味觉-mGluR4)检测，而其他L氨基酸(例如L-精氨酸)由一个受体(T1R1/T1R3)检测。具体目标1将确定三种L氨基酸(L-谷氨酸、L-精氨酸和L-丙氨酸)在野生型和T1R3基因敲除小鼠中的味道品质有多相似，方法是评估：a)这些物质的味觉阈值，b)使用条件味觉厌恶方法评估这些物质之间的知觉相似性，以及c)使用辨别方法评估这些物质之间的知觉差异。特定目标2将使用相同的行为方法在野生型和T1R3基因敲除小鼠中检测mGluR4拮抗剂对这些氨基酸味道质量的影响。这些用基因敲除和野生型小鼠进行的实验所产生的行为特征将为T1R3和味觉-mGluR4受体在这些氨基酸的传入信号中的作用提供新的见解。当将这些味觉转导机制应用于营养障碍个体(例如，糖尿病患者、心血管疾病、老年人)的食物摄入量调节时，这些味觉转导机制的理解可以具有巨大的保健意义。

DESCRIPTION (provided by applicant): Primary taste sensations (sweet, sour, bitter, salt, and umami) are often associated with different types of foods. For example, umami taste often signals food rich in proteins and certain L-amino acids. However, the basis of these sensations is controversial and not well understood. Molecular and limited behavioral studies have identified a candidate taste receptor, T1R1/T1R3, which detects umami stimuli, including monosodium glutamate, and many more L-amino acids. In contrast, other molecular and behavioral studies report evidence that L-AP4 (a potent mGluR4 agonist) elicits afferent signals that mimic umami stimulation, suggesting that a taste-mGluR4 receptor is involved in umami taste. This controversy is fueled by studies with mice lacking T1R3. One study reported that T1R3 knockout mice completely eliminated umami taste (Zhao et al., 2003), whereas another study with independently developed T1R3 knockout mice reported only a reduction in umami taste (Damak et al., 2003). Pilot threshold experiments with T1R3 knockout mice obtained from Damak et al. found that these mice can taste monosodium glutamate nearly as well as wild type mice of the same genetic background. In addition, preliminary studies with rats show that mGluR4 antagonists alter the taste of L-glutamate but have little effect on the taste of the amino acid L-arginine. These data, along with other studies, suggest that receptors other than T1R3 contribute to umami taste. Two Specific Aims in this proposal will test the hypothesis that some L-amino acids (e.g., L-glutamate) are detected by two receptors (T1R1/T1R3, taste-mGluR4) and other L-amino acids (e.g., L-arginine) are detected by one receptor (T1R1/T1R3). Specific Aim 1 will determine how similar the taste qualities of three L-amino acids (L-glutamate, L-arginine, and L-alanine) are in wild type and T1R3 knockout mice by assessing: a) taste thresholds for these substance, b) perceptual similarities between these substances using conditioned taste aversion methods, and c) perceptual differences between these substances using discrimination methods. Specific Aim 2 will examine the effects of mGluR4 antagonists on the taste qualities of these amino acids in wild type and T1R3 knockout mice using the same behavioral methods. The behavioral profiles developed from these experiments with knockout and wild-type mice will provide new insights into the roles of T1R3 and taste-mGluR4 receptors in afferent signaling of these amino acids. An understanding of these taste transduction mechanisms can have tremendous health care implications when applied to regulation of food intake by nutritionally challenged individuals (e.g., diabetics, cardiovascular disease, aged).