A novel ryanodine receptor in the hormonal regulation of hepatic metabolism

肝脏代谢激素调节中的新型兰尼定受体

• 批准号: 8058627
• 负责人: ANDREW P THOMAS
• 金额: $ 19.31万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058627
• 关键词: Biochemical; Brain; Caffeine; Calcium Signaling; Catecholamines; Cells; Chinese Hamster Ovary Cell; Cholestasis; Complex; Cyclic ADP-Ribose; Disease; Dose; Endocrine; Epithelium; Feedback; Frequencies; Gastrointestinal tract structure; Gene Expression; Generations; Genes; Health; Hepatic; Hepatitis; Hepatocyte; Hormonal; Hormones; ITPR1 gene; Inositol; Investigation; Length; Liver; Mediating; Metabolism; Molecular Structure; Muscle; Pancreas; Pancreatitis; Pathway interactions; Pattern; Physiological; Play; Process; Property; Protein Isoforms; Proteins; Public Health; Rattus; Regulation; Role; RyR1; Ryanodine; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Second Messenger Systems; Secretory Cell; Series; Signal Pathway; Signal Transduction; Signaling Protein; Site; Tissues; Vasopressins; Work; cell preparation; hormone regulation; improved; inhibitor/antagonist; innovation; liver function; new therapeutic target; novel; public health relevance; receptor; response; second messenger

DESCRIPTION (provided by applicant): The effects of hormones such as catecholamines and vasopressin on hepatic metabolism and secretion are mediated by alterations in the concentration of cytosolic free Ca2+ ([Ca2+]c), largely as a result of Ca2+ mobilization from intracellular stores by the second messenger inositol 1,4,5-trisphosphate (IP3). The [Ca2+]c signals elicited by these hormones are organized in the form of [Ca2+]c oscillations and waves, whose frequency is controlled by hormone dose. Frequency-modulated [Ca2+]c oscillations may serve a number of regulatory functions, including improved fidelity, sensitivity and targeted regulation of specific processes. While the role of IP3-receptors in this pathway is well established, it has recently become evident that other Ca2+ release and Ca2+-feedback components contribute to extend the temporal and spatial range of [Ca2+]c oscillations. One way in which this might be achieved is through interplay between IP3R and the other major class of intracellular Ca2+ release channels, the ryanodine receptors (RyRs). RyRs are typically activated by Ca2+ through a Ca2+-induced Ca2+ release (CICR) mechanism, but they can also be activated by another second messenger, cyclic-ADPribose (cADPR). Although the RyRs have been well-characterized in excitable tissues (primarily muscle and brain), relatively little is known about the identity and properties of RyRs in nonexcitable cells. We have recently identified and cloned a unique RyR isoform from rat hepatocytes (RyR1b), which is derived from the RyR1 gene, but with an alternative start site that gives rise to a protein of only 40% the size of full length muscle RyRs. We hypothesize that RyR1b has distinct functional properties that underlie its contribution to [Ca2+]c signaling in hepatocytes and other nonexcitable secretory cells, where it may be the principal RyR isoform. Specifically, we propose that RyR1b plays a key role in enhancing and sustaining ER Ca2+ release initiated by IP3R activation. We will examine the potential role of RyR1b in two specific aims: In Aim 1 we will carry out heterologous expression studies to investigate the function and regulatory properties of RyR1b, including regulation by [Ca2+]c, cADPR and its interactions with IP3 and the IP3R. In Aim 2 we will investigate the subcellular distribution and regulation of RyR1b in primary hepatocytes, and determine how it contributes to the temporal and spatial pattern of [Ca2+]c signaling during hormonal stimulation of these cells. RyR1b appears to be a major new addition to the superfamily of intracellular Ca2+ release channels, with distinct properties. It may have specific functions that are tuned to the signaling requirements of nonexcitable secretory epithelia and endocrine cells. Thus, the proposed work is innovative and has the potential for high impact, with significant biomedical health relevance. PUBLIC HEALTH RELEVANCE: The proposed work will investigate the role and regulation of a newly discovered calcium signaling protein (RyR1b) that appears to play a role in mediating the effects of hormones on liver function. It is also postulated to participate in signaling in other tissues, including the pancreas and cells of the digestive tract. Since derangements of signaling in these tissues are frequently associated with disease states (eg. hepatitis, cholestasis, pancreatitis), characterization of the properties of RyR1b has significant potential public health impact. Its unique molecular structure may yield a novel therapeutic target.

描述（由申请人提供）：激素如儿茶酚胺的作用 和加压素对肝代谢和分泌的影响是由胞质游离Ca 2+（[Ca 2 +]c）浓度的改变介导的，这主要是由于第二信使1，4，5-三磷酸肌醇（IP 3）从细胞内储存的Ca 2+动员的结果。由这些激素引起的[Ca 2 +]c信号以[Ca 2 +]c振荡和波的形式组织，其频率由激素剂量控制。频率调制的[Ca 2 +]c振荡可以提供许多调节功能，包括改善保真度，灵敏度和特定过程的靶向调节。虽然IP 3-受体在这一途径中的作用是公认的，它最近变得很明显，其他Ca 2+释放和Ca 2+反馈组件有助于扩展[Ca 2 +]c振荡的时间和空间范围。其中一种可能实现的方式是通过IP 3R和细胞内Ca 2+释放通道的另一个主要类别，兰尼碱受体（RyRs）之间的相互作用。RyR通常通过Ca 2+诱导的Ca 2+释放（CICR）机制被Ca 2+激活，但它们也可以被另一种第二信使环腺苷三磷酸（cADPR）激活。虽然RyR在可兴奋组织（主要是肌肉和大脑）中已经得到了很好的表征，但对RyR在非兴奋细胞中的身份和性质知之甚少。我们最近从大鼠肝细胞中鉴定并克隆了一种独特的RyR亚型（RyR 1b），该亚型源自RyR 1基因，但具有替代起始位点，产生的蛋白质大小仅为全长肌肉RyR的40%。我们假设RyR 1b具有独特的功能特性，这些特性是其对肝细胞和其他非兴奋性分泌细胞中[Ca 2 +]c信号传导的贡献的基础，在这些细胞中，它可能是主要的RyR亚型。具体来说，我们建议RyR 1b在增强和维持由IP 3R激活启动的ER Ca 2+释放中起着关键作用。我们将研究RyR 1b在两个特定目标中的潜在作用：在目标1中，我们将进行异源表达研究以研究RyR 1b的功能和调节特性，包括[Ca 2 +]c，cADPR及其与IP 3和IP 3R的相互作用的调节。在目的2中，我们将研究RyR 1b在原代肝细胞中的亚细胞分布和调节，并确定它如何有助于这些细胞激素刺激期间[Ca 2 +]c信号传导的时空模式。RyR 1b似乎是细胞内钙释放通道超家族的一个主要新成员，具有独特的特性。它可能具有特定的功能，这些功能与不可兴奋的分泌上皮细胞和内分泌细胞的信号需求相协调。因此，拟议的工作是创新的，有可能产生很大的影响，具有重大的生物医学健康意义。 公共卫生关系：这项工作将研究一种新发现的钙信号蛋白（RyR 1b）的作用和调节，该蛋白似乎在介导激素对肝功能的影响方面发挥作用。它也被假定参与其他组织中的信号传导，包括胰腺和消化道细胞。由于这些组织中信号的紊乱通常与疾病状态（例如，肝炎、胆汁淤积、胰腺炎），RyR 1b特性的表征具有显著的潜在公共卫生影响。其独特的分子结构可能产生新的治疗靶点。