Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet/umami taste receptors.
Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet/umami taste receptors.
复制标题
DOI：
10.7554/elife.84291
复制
发表时间：
2023-02-28
期刊：
影响因子：
7.7
通讯作者：
Yamashita, Atsuko
中科院分区：
文献类型：
--
作者：
Atsumi, Nanako;Yasumatsu, Keiko;Takashina, Yuriko;Ito, Chiaki;Yasui, Norihisa;Margolskee, Robert F.;Yamashita, Atsuko
盐的味觉是多方面的：低浓度或高浓度的NaCl通过不同的途径被优选或厌恶地感知。Cl−被认为通过一种未知的机制参与味觉。在这里，我们描述了Cl−离子结合和味觉受体1型（T1 r）的反应，这是一个由甜味/鲜味受体组成的受体家族。来自青鳉鱼的T1 r2 a/T1 r3异二聚体，目前唯一适合结构分析的T1 r，在T1 r3的配体结合结构域（LBD）的氨基酸结合位点附近表现出特异性Cl−结合，这可能在包括人类T1 r3在内的物种中是保守的。Cl−结合诱导T1 r2 a/T1 r3 LBD在亚到低mM浓度下的构象变化，类似于典型的味道物质。此外，小鼠口服Cl−增加了与表达T1 r的味觉细胞相连的味觉神经的脉冲频率，并促进了它们的行为偏好，这些行为偏好被T1 r特异性阻断剂或T1 r3敲除所减弱。这些结果表明，Cl−通过与T1 r结合来唤起味觉，从而在低浓度下作为另一种优选的咸味通路。当舌头表面的味觉受体蛋白质被食物分子激活时，人类就会感知到味觉。这些受体开启神经细胞，发送信号，大脑可以读取甜，酸，咸，苦或鲜味，这取决于哪个受体被激活。大多数有脊椎的动物都有相同的五种味觉感受器。在食物中，咸味通常是添加食盐的结果，食盐有两种成分：钠离子和氯离子。向大脑发出食物咸的信号的主要味觉受体在与钠离子结合时被激活。然而，一些研究表明，当食用微量时，盐也被认为是甜的。为什么会发生这种情况还不清楚，但有可能是盐的氯化物一半驱动了甜味。2017年，科学家们研究出了鱼类味觉受体的结构，相当于人类的甜味受体。奇怪的是，这种受体的一部分，称为T1 r2 a/T1 r3 LBD，与氯离子结合。这促使Atsumi，Yaspersu等人思考盐的“甜味"，导致他们更仔细地观察T1 r2 a/T1 r3 LBD以及氯化物是否真的可以激活它。Atsumi，Yaspersu等人使用结构生物学技术检查T1 r2 a/T1 r3 LBD，并发现证据表明受体可能与氯化物结合。进一步的生物物理学实验证实，氯确实与受体结合，并且它也会导致它改变形状。通常，形状的变化是受体激活的标志，这表明氯化物可以激活T1 r2 a/T1 r3 LBD。接下来，Atsumi，Yassudsu等人通过使用一种称为电生理学的方法来测量小鼠中这些神经元的活动，检查氯化物是否可以刺激当食物尝起来甜时发出信号的神经元。结果表明，当将含有少量氯化物的溶液置于小鼠的舌头上时，神经元变得活跃。当一种可以阻断受体活性的化合物与氯化物一起输送时，这种活性就消失了。此外，当小鼠选择白开水或含氯化物的水时，它们似乎更喜欢后者。这证实了小鼠通过激活甜味受体和神经元来识别氯化物的甜味。基于这些发现，Atsumi，Yassunsu等人提出，少量的盐可能尝起来是甜的，因为盐中的氯离子激活了甜味受体及其相关的神经元。他们的研究结果还表明，动物以多种方式感知盐，可能是因为平衡的盐水平对身体正常工作至关重要。未来对人类味觉受体的实验可能会揭示这些途径如何帮助评估人类的盐水平。
Salt taste sensation is multifaceted: NaCl at low or high concentrations is preferably or aversively perceived through distinct pathways. Cl− is thought to participate in taste sensation through an unknown mechanism. Here, we describe Cl− ion binding and the response of taste receptor type 1 (T1r), a receptor family composing sweet/umami receptors. The T1r2a/T1r3 heterodimer from the medaka fish, currently the sole T1r amenable to structural analyses, exhibited a specific Cl− binding in the vicinity of the amino-acid-binding site in the ligand-binding domain (LBD) of T1r3, which is likely conserved across species, including human T1r3. The Cl− binding induced a conformational change in T1r2a/T1r3LBD at sub- to low-mM concentrations, similar to canonical taste substances. Furthermore, oral Cl− application to mice increased impulse frequencies of taste nerves connected to T1r-expressing taste cells and promoted their behavioral preferences attenuated by a T1r-specific blocker or T1r3 knock-out. These results suggest that the Cl− evokes taste sensations by binding to T1r, thereby serving as another preferred salt taste pathway at a low concentration. Humans perceive taste when proteins called taste receptors on the surface of the tongue are activated by molecules of food. These receptors turn on nerve cells that send signals the brain can read as sweet, sour, salty, bitter, or umami, depending on which receptor was activated. Most animals with backbones share the same five types of taste receptors. In food, salty flavors are usually the result of adding table salt, which has two components: a sodium ion and chloride ion. The main taste receptors that signal to the brain that a food is salty become activated when they bind to the sodium ion. However, some studies have shown that salt is also perceived as sweet when eaten in minuscule amounts. It is poorly understood why this happens, but it is possible that the chloride half of salt drives the sweet taste. In 2017, scientists worked out the structure of a taste receptor from a fish, that is equivalent to the sweet receptor in humans. Curiously, one part of this receptor, known as T1r2a/T1r3LBD, was bound to a chloride ion. This prompted Atsumi, Yasumatsu et al. to think about the ‘sweet’ taste of salt, leading them to take a closer look at T1r2a/T1r3LBD and whether chloride could indeed activate it. Atsumi, Yasumatsu et al. used structural biology techniques to examine T1r2a/T1r3LBD and found evidence that the receptor might be binding chloride. Further biophysical experiments confirmed that chloride does indeed bind to the receptor, and that it also causes it to change shape. Usually, changes in shape are hallmarks of receptor activation, suggesting that chloride may activate T1r2a/T1r3LBD. Next, Atsumi, Yasumatsu et al. checked whether chloride could stimulate the neurons that signal when food tastes sweet, by using an approach known as electrophysiology to measure the activity of these neurons in mice. The results showed that the neurons became active when a solution containing small amounts of chloride was placed on the mouse’s tongue. This activity went away when a compound that can block the receptor’s activity was delivered alongside the chloride. Additionally, when mice were given a choice of plain water or water containing chloride, they seemed to prefer the latter. This confirmed that mice recognized the sweetness of chloride via the activation of sweet taste receptors and neurons. Based on these findings, Atsumi, Yasumatsu et al. propose that small amounts of salt may taste sweet because the chloride ions in the salt activate sweet taste receptors and their linked neurons. Their results also suggest that animals sense salt in many ways, likely because balanced salt levels are essential for the body to work properly. Future experiments on human taste receptors may reveal how these pathways help assess salt levels in humans.