Molecular determinants of ACTH receptor for ligand binding

ACTH 受体配体结合的分子决定因素

• 批准号: 6956330
• 负责人: YINGKUI YANG
• 金额: $ 7.26万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956330
• 关键词: adrenal disorder; adrenocorticotropic hormone; biological signal transduction; cell surface receptors; flow cytometry; hormone binding protein; hormone receptor; ligands; polymerase chain reaction; radioimmunoassay; receptor expression

DESCRIPTION (provided by applicant): The adrenocorticotropic hormone (ACTH) receptor, also known as the melanocortin-2 receptor (MC2R), is a subtype of the melanocortin receptor family, which plays an important role in regulating and maintaining adrenocortical function, specifically steroidogenesis. Mutations of the human MC2R (hMC2R) gene have been demonstrated in human with familial glucocorticoid deficiency. It presents in childhood with failure-to thrive, weakness, fatigue and possible adrenal crisis. Therefore, a better understanding of the molecular basis of hMG2R is important to understanding the physiology and pathology of hMC2R function. It is also critical in developing effective therapeutic strategies for the treatment of important human adrenal disorders. The hMC2R is homologous to the other 4 cloned melanocortin receptors, which together form a distinct subfamily of 7 transmembrane domain G protein-coupled receptors (GPCR). Within the past several years we and other investigators have performed extensive studies to determine the molecular basis of ligand receptor interaction between the melanocortin family of peptides (including agonist a-MSH, ACTH, and antagonist Agouti signaling protein (ASIP), Agouti-related protein (AGRP)) and the melanocortin receptors. However, the molecular determinants of MC2R responsible for agonist ACTH and antagonist ASIP binding and action remain unclear. This proposal is directed towards examining the molecular determinants of hMC2R responsible for ligand binding and receptor activation. Based on our previous work with other melanocortin receptors, we hypothesize that: 1) transmembrane domains of hMC2R play important roles in agonist ACTH binding and receptor activation and 2) both extracellular loops and transmembrane domains of hMC2R are crucial for antagonist ASIP binding and activity. To test this hypothesis we will utilize the hMC2R mutagenesis and chimeric receptor studies to determine the molecular basis of hMC2R ligand receptor interaction. The proposed studies will provide important information needed to fill in the gap in our current knowledge of the molecular determinants of hMC2R responsible for ligand binding and receptor activation. The information will serve to establish a foundation on which to build a comprehensive understanding of the signaling events that regulate ACTH mediated adrenal function in physiologic and diseased states.

描述（由申请人提供）：促肾上腺皮质激素（ACTH）受体，也称为黑皮质素-2受体（MC 2 R），是黑皮质素受体家族的一种亚型，在调节和维持肾上腺皮质功能，特别是类固醇生成中发挥重要作用。人类MC 2 R（hMC 2 R）基因突变已在家族性糖皮质激素缺乏症患者中得到证实。它在儿童时期表现为发育不良、虚弱、疲劳和可能的肾上腺危象。因此，更好地理解hMG 2 R的分子基础对于理解hMC 2 R功能的生理和病理是重要的。这也是至关重要的，在制定有效的治疗策略，治疗重要的人类肾上腺疾病。hMC 2 R与其他4种克隆的黑皮质素受体同源，它们共同形成7个跨膜结构域G蛋白偶联受体（GPCR）的不同亚家族。在过去的几年中，我们和其他研究人员进行了广泛的研究，以确定黑皮质素家族的肽（包括激动剂α-MSH、ACTH和拮抗剂Agonists信号传导蛋白（ASIP）、Agouti相关蛋白（AGRP））与黑皮质素受体之间的配体受体相互作用的分子基础。然而，负责激动剂ACTH和拮抗剂ASIP结合和作用的MC 2 R的分子决定因素仍不清楚。该提议针对检查负责配体结合和受体活化的hMC 2 R的分子决定簇。基于我们以前对其他黑皮质素受体的研究，我们假设：1）hMC 2 R的跨膜结构域在激动剂ACTH结合和受体活化中起重要作用，2）hMC 2 R的细胞外环和跨膜结构域对于拮抗剂ASIP结合和活性至关重要。为了验证这一假设，我们将利用hMC 2 R诱变和嵌合受体研究来确定hMC 2 R配体受体相互作用的分子基础。提出的研究将提供重要的信息，需要填补差距，在我们目前的知识的分子决定簇的hMC 2 R负责配体结合和受体活化。这些信息将有助于建立一个基础，在此基础上建立一个全面的了解信号事件，调节促肾上腺皮质激素介导的肾上腺功能的生理和疾病状态。