Physiology and regulation of T2R bitter taste receptors in enteroendocrine cells

肠内分泌细胞T2R苦味受体的生理学和调节

• 批准号: 8528267
• 负责人: Timothy F Osborne
• 金额: $ 42.41万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528267
• 关键词: ABCB1 gene; Accidents; Address; Adopted; Agonist; Animals; Area; Biological Assay; Cell Line; Cell Surface Receptors; Cells; Cholecystokinin; Cholesterol; Coupled; Deglutition; Diet; Dietary Cholesterol; Discrimination; Eating; Enterocytes; Enteroendocrine Cell; Enzyme-Linked Immunosorbent Assay; Epithelium; Exons; Family; Food; Gastrins; Gastrointestinal tract structure; Genes; Genetic; Genetic Models; Hepatic; Hormones; Human; In Situ; Individual; Ingestion; Intestinal Secretions; Intestines; Islets of Langerhans; Knock-out; Lovastatin; Lung; Mammals; Measures; Mediating; Methods; Molecular; Monitor; Mus; Mutant Strains Mice; Mutation; Oral; Oral cavity; Organ Culture Techniques; Pancreas; Pathway interactions; Peptides; Physiological; Physiology; Plants; Poison; Polypeptide Hormones; Proteins; Publications; Receptor Cell; Receptor Gene; Receptor Signaling; Regulation; Relative (related person); Rodent; Role; SRE-2 binding protein; Savory; Signal Transduction; Small Intestines; Source; Stomach; Surface; TRPM5 gene; Taste Perception; Testing; Tongue; Toxin; Work; absorption; airway epithelium; base; cell motility; cholesterol absorption; design; detection of nutrient; ezetimibe; feeding; glucagon-like peptide; glucagon-like peptide 1; in vivo; monomer; mouse model; novel; oral tissue; peptide hormone; prevent; promoter; public health relevance; receptor; receptor coupling; response; small molecule; sweet receptor; sweet taste perception; transcription factor; uptake

DESCRIPTION (provided by applicant): Mammals recognize bitter constituents in food through individual small "bitter" molecule agonists stimulation of individual cell surface receptors. These taste 2 receptors (T2Rs) are encoded by a family of single-exon g- protein coupled receptor (GPCR) genes and are predominantly expressed in taste receptor cells (TRCs) on the surface of the tongue and surrounding oral tissue. There is a lone GPCR involved in the majority of sweet taste sensing which is a heterodimer of Taste 1 Receptor (T1R) monomers T1R2 and T1R3. The single sweet and the entire family of bitter T2 receptors are also expressed in areas outside of the oral cavity including the lung, pancreas, and small intestine. Their function in the tongue is obviously to allow taste discrimination between differen potential food sources, however, the physiologic role for taste receptors outside of the oral cavity is not intuitively obvious. In recent publications, we showed that activation of intestinal T2R signaling leads to an increase in secretion of polypeptide hormones cholecystokinin (CCK) and glucagon-like-peptide-1 (GLP-1) from enteroendocrine cells and two major actions of CCK are to limit food intake and slow gastric motility. These results suggest intestinal T2Rs may limit absorption of bitter and potentially toxic molecules that are ingested despite the taste aversion in the mouth. We also showed that intestinal expression and activity of the T2Rs is regulated by the sterol regulatory element binding protein -2 (SREBP-2) transcription factor, which is induced when cellular cholesterol levels are low and activates genes required for accumulating new cell cholesterol. Plant enriched diets are both low in cholesterol and have a higher proportion of bitter tasting and potentially toxic substances relative to diets rich in cholesterol-laden animal flesh. Thus, induction of T2R activity through SREBP-2 on low-cholesterol plant diets provides a mechanism to "sensitize" the gut to the presence of potentially toxic molecules to limit their absorption through CCK dependent suppression of both gut motility and food in take. It should be noted that CCK and the gut peptide hormone gastrin have identical carboxyl termini and the ELISA we used in our early studies detects both hormones with similar sensitivity. Thus, gastrin may be the relevant hormone that is induced by T2R signaling in the gut and our current project is designed to address this key issue. We also showed CCK/gastrin increases expression and activity of the ABCB1 efflux transporter, which is known to prevent cellular uptake of a wide range of toxic organic small molecules. This provides a more active mechanism to limit absorption of toxic molecules consumed during a meal or by accident. Taken together, these studies provide a molecular mechanism connecting nutrient sensing with protection from toxin ingestion. The current proposal combines physiologic studies in select mouse models that have mutations in genes encoding critical proteins of the nutrient sensing and toxin efflux pathways to rigorously test the mechanism. We also propose to adopt a novel in situ assay with isolated small intestine to monitor the connection between T2R signaling and toxin efflux directly.

描述（由申请人提供）：哺乳动物通过单个小的“苦”分子激动剂刺激单个细胞表面受体来识别食物中的苦成分。这些味觉2受体（T2Rs）由一个单外显子g蛋白偶联受体（GPCR）基因家族编码，主要在舌头表面和周围口腔组织的味觉受体细胞（TRCs）中表达。有一种单独的GPCR参与了大多数甜味感知，它是味觉1受体（T1R）单体T1R2和T1R3的异源二聚体。单一的甜味和整个苦味T2受体家族也在口腔外的区域表达，包括肺、胰腺和小肠。它们在舌头上的功能显然是让味觉区分不同的潜在食物来源，然而，口腔外味觉受体的生理作用并不直观明显。在最近的出版物中，我们发现肠道T2R信号的激活导致肠内分泌细胞中多肽激素胆囊收缩素（CCK）和胰高血糖素样肽-1 （GLP-1）的分泌增加，CCK的两个主要作用是限制食物摄入和减缓胃蠕动。这些结果提示肠道t2r可能会限制