Nicotinic Acetylcholine Receptor Mediated Bitter Taste Transduction

烟碱乙酰胆碱受体介导的苦味转导

• 批准号: 8675220
• 负责人: Vijay Lyall
• 金额: $ 30.19万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675220
• 关键词: Acetylcholine; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Animal Model; Antibodies; Automobile Driving; Behavioral; Binding; Cations; Cells; Chronic; Coupled; Cues; Data; Detection; Drosophila acetylcholine receptor alpha-subunit; Drug usage; Enzymes; Esthesia; Ethanol; Event; Exposure to; Figs - dietary; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Genetic Polymorphism; Human; In Situ Hybridization; Inbred Strains Mice; Ion Channel; Knockout Mice; Link; Malignant neoplasm of lung; Measures; Mecamylamine; Mediating; Messenger RNA; Molecular; Monitor; Mus; Nasal cavity; Nerve; Neuraxis; Nicotine; Nicotine Dependence; Nicotinic Receptors; Patch-Clamp Techniques; Pathway interactions; Peripheral; Phenylthiourea; Play; Positive Reinforcements; Predisposition; Quinine; Rattus; Receptor Cell; Receptor Gene; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Role; Saliva; Sensory; Signal Pathway; Smoke; Smoker; Smoking; Sprague-Dawley Rats; Stream; System; TRPM5 gene; Taste Bud Cell; Taste Buds; Taste Perception; Techniques; Testing; Tobacco; Work; addiction; alcohol response; alcohol use disorder; chorda tympani; cigarette smoking; erythroidine; food consumption; mRNA Expression; preference; rat Gnat3 protein; receptor; relating to nervous system; response; sensory system; therapeutic target; voltage clamp

DESCRIPTION (provided by applicant): Every year, more than 5 million people die primarily from developing smoking related lung cancer. Tobacco contains nicotine, the major compound responsible for driving the strong addiction to smoking. Nicotine is addictive because of its effects on the central nervous system mediated by nicotinic acetylcholine receptors (nAChRs). The ability to sense the bitter taste of phenylthiocarbamide due to polymorphisms in a taste receptor gene (T2R38) protects a subject from developing a cigarette smoking addiction and reduces the positive reinforcement from smoking. This suggests that changes in taste play a significant role in the context of cigarette smoking and provide important cues involved in nicotine addiction. Although nicotine is described as bitter tasting, the molecular and cellular mechanisms that encode the taste of nicotine remain unclear. Our studies show that nicotine activates the taste system via two parallel receptor-mediated pathways. One pathway involves a G-protein coupled receptor (T2R) and down stream effectors (a G-protein gustducin, an enzyme PLC¿2 and a cation channel, TRPM5) that are common to sweet, bitter and umami bitter sensing. The second pathway utilizes nAChRs and responds to nicotine, acetylcholine, ethanol and perhaps other bitter tastants and is essential for their complete sensory representation. The overall aim of this study is to increase our understanding of the contribution of different nAChR subunits to the bitter taste of nicotine, acetylcholine, ethanol and other bitter compounds. Studies are designed to investigate the presence of different nAChR subunits in taste bud cells using molecular techniques (RT-PCR, quantitative-RT-PCT, immunohistochemical and in situ hybridization). To investigate the role of nAChRs in peripheral taste transduction we will monitor the effects of pharmacological agonists and antagonists of nAChRs on single isolated taste cells using whole cell patch clamp technique, chorda tympani taste nerve responses and on lick rates as a measure of altered behavioral responses to nicotine, acetylcholine, ethanol and other bitter tastants in several animal models. Specifically, we will use genetically modified mice in which specific nAChR subunit genes or genes for TRPM5 cation channel have been deleted. The information obtained in this study on the nAChR-dependent bitter- sensing pathway may provide us with information regarding taste-related events that may be either involved in or predictors of nicotine and alcohol addiction. The effects of cigarette smoking on food consumption and taste preferences may occur from peripheral taste modulation due to chronic exposure to nicotine acting on nAChRs in taste buds among other factors.

描述（由申请人提供）：每年有超过 500 万人主要死于与吸烟相关的肺癌。烟草中含有尼古丁，尼古丁是导致强烈吸烟成瘾的主要化合物，因为它对中枢神经系统有影响。由烟碱乙酰胆碱受体 (nAChR) 介导的神经系统 由于味觉受体基因的多态性而能够感知苯硫脲的苦味。 (T2R38) 可以保护受试者免于吸烟成瘾，并减少吸烟带来的积极强化，这表明味觉的变化在吸烟过程中发挥着重要作用，并提供了与尼古丁成瘾有关的重要线索。苦味，编码尼古丁味道的分子和细胞机制仍不清楚。我们的研究表明，尼古丁通过两个平行的受体介导的途径激活味觉系统，其中一个途径涉及 G 蛋白偶联受体 (T2R) 和下游。效应子（G蛋白味素、酶PLC¿ 2 和阳离子通道 TRPM5）是甜味、苦味和鲜味感知所共有的第二条途径利用 nAChR 并对尼古丁、乙酰胆碱、乙醇和可能的其他苦味促味剂做出反应，对于其完整的感官表征至关重要。这项研究的目的是加深我们对不同 nAChR 亚基对尼古丁、乙酰胆碱、乙醇和其他苦味化合物的苦味贡献的了解。旨在使用分子技术（RT-PCR、定量 RT-PCT、免疫组织化学和原位杂交）研究味蕾细胞中不同 nAChR 亚基的存在。为了研究 nAChR 在外周味觉转导中的作用，我们将监测其影响。使用全细胞膜片钳技术、鼓索味觉神经反应和舔率作为改变行为反应的量度，对单个分离的味觉细胞上的 nAChR 药理学激动剂和拮抗剂进行研究具体来说，我们将使用转基因小鼠，其中特定的nAChR亚基基因或TRPM5阳离子通道基因已被删除，从而获得有关nAChR依赖性苦味的信息。 - 传感途径可以为我们提供有关味觉相关事件的信息，这些事件可能涉及或预测尼古丁和酒精成瘾。吸烟对食物消耗和味觉偏好的影响可能来自外周。由于长期接触尼古丁而对味蕾中的 nAChR 产生作用，从而导致味觉调节。