TRPC1, Calcium, and Saliva Secretion

TRPC1、钙和唾液分泌

• 批准号: 8664243
• 负责人: Brij B Singh
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664243
• 关键词: Adenoviruses; Adverse effects; Affect; Agonist; Autoimmune Diseases; Award; Biological Process; Calcium; Calcium Channel; Cell Culture Techniques; Cell Line; Cell membrane; Cells; Chloride Channels; Collaborations; Complex; Deglutition; Disease; Drug Targeting; Etiology; Event; Fluids and Secretions; Functional disorder; Funding; Goals; Grant; Head and Neck Cancer; Human; Individual; Intervention; Ion Channel; Mastication; Mediating; Membrane Microdomains; Modeling; Molecular; Mus; Oral; Oral cavity; Oral health; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Population; Positioning Attribute; Potassium Channel; Potassium Chloride; Proteins; Radiation therapy; Regulation; Regulatory Pathway; Research; Research Project Grants; Role; STIM1 gene; Saliva; Salivary Gland Tissue; Salivary Glands; Signal Transduction; Signaling Protein; Sodium; Speech; Stimulus; Submandibular gland; Syndrome; Taste Perception; Testing; Therapeutic Intervention; Tissues; Up-Regulation; base; cancer therapy; in vivo; insight; overexpression; protein aggregate; protein protein interaction; receptor; response; saliva secretion; sensor; soft tissue; symporter; therapeutic target; tool; water channel

DESCRIPTION (provided by applicant): Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral health. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction. Secretion of saliva is driven by concerted activities of a number of ion channels and transporters. Although, it is believed that calcium is the primary intracellular factor that regulates fluid secretion, the molecular mechanism involved in the regulation of cytosolic calcium is not clearly understood. This is primarily due to the lack of information regarding the mechanism of regulation of calcium channels present in salivary glands. Furthermore, no information is available as how increase in cytosolic calcium modulates saliva secretion. Moreover, in Sj"gren's syndrome patients, although the acinar tissues appear to be normal, they do not function properly and have a decreased calcium response to agonist-stimulation. This observation raises the possibility that calcium channels might be altered in this pathological condition. Results obtained from our awarded grant indicate that TRPC1 is the primary calcium channel in salivary glands and is intimately involved saliva secretion. To understand the regulation of TRPC1 channel we have shown that in human submandibular gland cells, TRPC1 interaction with STIM1, Cav1, and Orai1 dictates TRPC1 mediated calcium entry. Furthermore, these protein-protein interactions were confined to specific domains in the plasma membrane, however nothing is known if similar mechanisms are also present in vivo in salivary gland tissues. Therefore, in this renewal we intend to thoroughly characterize the role of cytosolic calcium in salivary gland function and to determine the relationship between transient receptor potential canonical (TRPC1) -1 and saliva secretion. The hypothesis of this study is that because calcium influx via TRPC1 plays a pivotal role in the physiological function of salivary glands, characterization of calcium channels in salivary glands will be important to understand the mechanism of saliva secretion, which could represent as drug targets in salivary gland dysfunction. We will coordinate our efforts in order to determine the functional significance of TRPC1 channel in regulating saliva secretion. We will also investigate the role of lipid rafts in the assembly/activation of the TRPC1 channel in mouse submandibular gland cells and will identify the mechanism involved in the regulation of TRPC1 via STIM1 and Orai1. The results of our studies are expected to provide new insights into the role of calcium channels and the molecular mechanism involved in saliva secretion. Greater understanding of these events responsible for saliva secretion will be important in elucidating new therapy for salivary gland dysfunctions.

描述（由申请人提供）：唾液执行许多非常重要的生物学功能，这些功能有助于维持口腔健康。据估计，美国有超过500万人患有唾液腺功能障碍。唾液的分泌是由许多离子频道和转运蛋白的一致活动驱动的。尽管人们认为钙是调节液体分泌的主要细胞内因子，但尚未清楚地理解与胞质钙调节有关的分子机制。这主要是由于缺乏有关唾液腺中存在的钙通道调节机理的信息。此外，没有信息可获得胞质钙如何调节唾液分泌。 Moreover, in Sj"gren's syndrome patients, although the acinar tissues appear to be normal, they do not function properly and have a decreased calcium response to agonist-stimulation. This observation raises the possibility that calcium channels might be altered in this pathological condition. Results obtained from our awarded grant indicate that TRPC1 is the primary calcium channel in salivary glands and is intimately involved saliva secretion. To understand the regulation of TRPC1通道我们已经表明，在人类的下腺细胞中，TRPC1与stim1，cav1和Orai1的相互作用决定了TRPC1介导的钙的进入，这些蛋白质 - 蛋白质相互作用局限于质膜中的特定域中胞质钙在唾液腺功能中的作用，并确定瞬态受体潜能（TRPC1）-1和唾液分泌之间的关系。作为唾液腺功能障碍的药物，我们将协调我们的努力，以确定TRPC1通道在调节唾液分泌的功能。对钙通道的作用和涉及唾液分泌的分子机制的见解。