SEROTONIN (5-HT) RECEPTORS AND SALIVARY GLAND FUNCTION

描述(改编自调查者摘要)：生物胺， 5-羟色胺(5-羟色胺，[5-HT])是一种重要的细胞外调节因子 在中枢神经系统和许多周围组织中，包括 胃肠道、尿路、肾上腺皮质和血管系统。 首席调查员实验室公布的数据表明 在完整灌流的大鼠颌下腺中，5-羟色胺降低 乙酰胆碱诱导唾液流动，增加唾液蛋白质含量。5-羟色胺 也增加了分散的SMG中cAMP的产生(以及舌下和 腮腺)细胞聚集，但对SMG细胞内游离钙离子无影响 浓度。这项提案中提出的数据表明，大鼠SMG 共同表达两种5-羟色胺受体亚型5-HT4b和5-HT7，这两种亚型都是 与营地生产正相关。这项提议的主要假设是 大鼠SMG内cAMP偶联的5-羟色胺受体在 腺体功能的调节。这种受体可能具有潜在的治疗作用。 影响唾液腺功能的疾病的靶点。世界银行的目标是 研究内容如下：1.明确大鼠SMG中5-羟色胺受体的补体 根据使用分子的亚型和每个亚型的受体密度， 药理学和放射性配基结合技术。2.确定 功能性5-羟色胺受体亚型的细胞类型特异性分布 SMG弥散导管和富含腺泡的细胞团中的分析 结合旨在共同定位5-羟色胺的原位杂交研究 利用DUAL技术获得带有细胞型特异性标记蛋白的受体亚型mRNAs 荧光技术，3.验证腺苷环化酶-cAMP-cAMP 依赖蛋白激酶信号通路介导5-羟色胺在大鼠脑内的作用 SMG，通过使用激活或抑制的选择性药理工具 该途径与亚型特异性的5-HTR配体结合； 开始评估SMG 5-羟色胺受体的生理相关性 测定腺体内5-羟色胺水平，检测关键的5-羟色胺合成 SMG中的酶及高亲和力5-羟色胺的存在和水平的测定 SMG中的转运蛋白(SERT)。成功完成这些目标将有助于 解决5-羟色胺是否是不断增长的代理之一的问题 参与哺乳动物唾液腺功能和能力的调节 激发患者对5-羟色胺受体作为治疗靶点的兴趣 唾液腺功能障碍。

DESCRIPTION (adapted from the Investigator's abstract): The biogenic amine, serotonin (5-hydroxytrptamine, [5-HT]) is an important extracellular regulator in the central nervous system and many peripheral tissues including the gastrointestinal tract, urinary tract, adrenal cortex, and vasculature. Published data from the Principal Investigator's laboratory have demonstrated that, in the intact perfused rat submandibular gland, 5-HT decreases acetylcholine-induced saliva flow and increases saliva protein content. 5-HT also increases cAMP production in dispersed SMG (as well as sublingual and parotid) cell aggregates, but has no effect on SMG cell intracellular free Ca2+ concentrations. The data presented in this proposal suggest that rat SMG co-expresses two 5-HT receptor subtypes, 5-HT4b and 5-HT7, both of which are positively coupled to cAMP production. The main hypothesis of this proposal is that cAMP-coupled 5-HT receptors in the rat SMG play physiological roles in the regulation of gland function. Such receptors might be potential therapeutic targets in diseases affecting salivary gland function. The goals of the research are: 1. To define conclusively the 5-HT receptor complement in rat SMG in terms of subtypes and receptor density of each subtype using molecular, pharmacological, and radioligand binding techniques. 2. To determine the cell-type specific distribution of 5-HT receptor subtypes using functional assays in dispersed duct and acinar -enriched cell aggregates from SMG in conjunction with in situ hybridization studies designed to co-localize 5-HT receptor subtype mRNAs with cell-type specific marker proteins using dual fluorescence techniques, 3. To verify that the adenyl cyclase-cAMP-cAMP dependent protein kinase signaling pathway mediates the 5-HT effects in the SMG, through use of selective pharmacological tools which activate or inhibit this pathway in conjunction with subtype-specific 5-HTR ligands; and 4. To begin to assess the physiological relevance of SMG 5-HT receptors by determining the 5-HT levels in the gland, detecting the key 5-HT synthetic enzyme in SMG and determining the presence and level of high affinity 5-HT transporters (SERT) in SMG. Successful completion of these goals will help to resolve the question of whether 5-HT is one of the growing list of agents involved in the regulation of mammalian salivary gland function and might stimulate interest in 5-HT receptors as therapeutic targets in patients with salivary gland dysfunction.