Adrenergic Receptor Linked ROS-GC Neurosensory Signaling

肾上腺素受体相关 ROS-GC 神经感觉信号转导

• 批准号: 6535969
• 负责人: RAMESHWAR K SHARMA
• 金额: $ 30.58万
• 依托单位: UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-20 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6535969
• 关键词: adrenergic receptor; binding proteins; biological signal transduction; calcium flux; cyclic GMP; guanylate cyclase; immunocytochemistry; immunoprecipitation; medial olfactory area; neural information processing; neural transmission; neurons; neurophysiology; olfactory lobe; respiratory epithelium; second messengers; sensory mechanism; sensory receptors

DESCRIPTION (provided by applicant): The proposed research presents a novel concept that provides a uniform signaling theme in sensory neurons. The central component of this theme is the ROS-GC transduction machinery. The machinery is operated by the fluxes in free Ca2+ arising inside the cellular compartment of the neuron. Each flux is sensed by a Ca2+ sensor component of the machinery, termed the transducer. The transducer then accelerates or inhibits the operational activity of the machinery. Acceleration causes an increment, and inhibition causes a decrement in the production of the second messenger cyclic GMP. It is then predicted that cyclic GMP, via a cyclic GMP-gated channel, regulates the degree of polarization of the sensory neuron. Specificity in acceleration or inhibition of the machinery resides in the nature of the transducer, of which there are two types-one type inhibiting and the other stimulating ROS-GC activity. Both transducer types belong to a family of Ca2+-binding proteins. GCAPs represent the inhibitory and CD-GCAPs the stimulatory type of the transducers. There are two forms of GCAPs:GCAP1 and GCAP2, and two of CD-GCAPs: S100beta and neurocalcin. Each subtype of the transducer exhibits its biological activity through the specified domain in ROS-GC with which it binds, and then either stimulates or inhibits the catalytic cyclase activity. ROS-GC exists in three forms: ROS-GC1, ROS-GC2 and ONE-GC. In this manner, composition of the ROS-GC transduction machinery defines its functional status and cellular specificity. Consistent with the proposed neurosignaling concept, the presented evidence shows that the ROS-GC transduction machinery exists in the sensory neurons of photoreceptors, olfaction, pinealocytes, and SCN. But its composition varies from cell to cell. The proposed Specific Aims are designed to test the "ROS-GC Transduction" concept in the model system of olfactory neurons. This system is composed of three distinct neuronal regions: 1) the olfactory neuroepithelium, 2) the olfactory bulb, and 3) the olfactory cortex. These neuronal regions will be analyzed at a physiological, biochemical, functional, and immunological level for the presence and composition of the ROS-GC transduction system; and a determination of the functional motif of each of the ROS-GCs for its transducer present in each of the respective region will be made. Through the years, a series of comprehensive immunological, genetic, biochemical and cell-specific probes have been developed against a variety of epitopes of the ROS-GC signal transduction components. These, and other soon to be developed tools, will be used to accomplish the specified aims. Although the proposed research is of a most fundamental nature, its biochemical ramifications in understanding the basic principles associated with the sensory perception of smell, vision, taste, and biological rhythms are numerous. it is envisioned that this knowledge will ultimately be applied in rectifying the pathologies associated with these neurosensory processes.

描述（由申请人提供）：拟议的研究提出了一个新颖的概念，在感觉神经元中提供统一的信号主题。该主题的核心组成部分是 ROS-GC 转导机制。该机器是通过神经元细胞室内产生的游离 Ca2+ 通量来操作的。每个通量由机械的 Ca2+ 传感器组件（称为传感器）感测。然后传感器加速或抑制机器的操作活动。加速会导致第二信使环 GMP 的产生增加，而抑制会导致第二信使环 GMP 的产生减少。然后预测循环 GMP 通过循环 GMP 门控通道调节感觉神经元的极化程度。机械加速或抑制的特异性取决于传感器的性质，其中有两种类型——一种是抑制型，另一种是刺激型 ROS-GC 活性。两种传感器类型均属于 Ca2+ 结合蛋白家族。 GCAP 代表抑制型传感器，CD-GCAP 代表刺激型传感器。 GCAP 有两种形式：GCAP1 和 GCAP2，CD-GCAP 有两种形式：S100beta 和神经钙素。转导器的每种亚型通过与其结合的 ROS-GC 中的特定结构域表现出其生物活性，然后刺激或抑制催化环化酶活性。 ROS-GC以三种形式存在：ROS-GC1、ROS-GC2和ONE-GC。通过这种方式，ROS-GC 转导机制的组成决定了其功能状态和细胞特异性。与提出的神经信号传导概念一致，所提供的证据表明 ROS-GC 转导机制存在于光感受器、嗅觉、松果体细胞和 SCN 的感觉神经元中。但其组成因细胞而异。所提出的具体目标旨在测试嗅觉神经元模型系统中的“ROS-GC 转导”概念。该系统由三个不同的神经元区域组成：1）嗅觉神经上皮，2）嗅球，3）嗅觉皮层。这些神经元区域将在生理、生化、功能和免疫学水平上进行分析，以了解 ROS-GC 转导系统的存在和组成；并且将确定每个 ROS-GC 的功能基序及其存在于每个相应区域中的转导器。多年来，针对 ROS-GC 信号转导成分的多种表位，开发了一系列全面的免疫学、遗传、生化和细胞特异性探针。这些以及其他即将开发的工具将用于实现指定的目标。尽管所提出的研究具有最基本的性质，但其在理解与嗅觉、视觉、味觉和生物节律等感官知觉相关的基本原理方面的生化影响是很多的。预计这些知识最终将应用于纠正与这些神经感觉过程相关的病理学。