Purinergic Receptors in Olfactory System

描述（由申请人提供）：最近的证据表明， 细胞外ATP在细胞信号传导中起着重要作用， 感觉系统中的神经调质伤害性刺激，细胞损伤和某些 病理生理条件可引起胞质ATP的释放。ATP可以结合 两种嘌呤受体之一：P2 Y G蛋白偶联受体或P2 X 离子通道形成受体。通过这些受体亚型中的任何一种，ATP被 能够引起细胞内Ca 2+（[Ca 2 +]i）的增加。[Ca2+]我有钥匙 调节嗅觉信号传导的敏感性。气味剂 与嗅觉受体神经元（ORN）上的特定受体结合， 激活G蛋白偶联腺苷酸环化酶/ cAMP第二信使级联， 导致cAMP门控（CNG）阳离子通道的顺序开放， [Ca2+]i. [Ca 2 +]i的增加在 作为嗅觉传导的第三信使。它能打开Ca 2+激活的Cl- 通道，实质上放大发电机电流。钙也会增加 通过调节CNG通道活性或 分子在转导级联中。因此，[Ca 2 +]i稳态的变化 可以改变ORN对刺激的反应。该应用程序将测试 一般假设，伤害性或三叉神经刺激的 外周嗅觉系统引起ATP的释放， 嗅觉受体神经元对气味的反应。它将提供第一个 详细的分子、药理学、电生理学和 嘌呤能核苷酸受体免疫荧光特性 外周哺乳动物的嗅觉结构，并将区分的作用， 核苷酸在嗅觉的控制、信号传导和调节中的作用。因为ATP是 在神经传递和有害刺激过程中释放，这些研究可能 阐明观察到的嗅觉敏感性降低的机制， 接触有毒物质

DESCRIPTION (provided by applicant): Recent evidence indicates that extracellular ATP plays an important role in cellular signaling and can act as a neuromodulator in sensory systems. Noxious stimuli, cell damage and certain pathophysiological conditions can evoke release of cytosolic ATP. ATP can bind to either of two purinergic receptors: P2Y G-protein-coupled receptors or P2X ion channel-forming receptors. Through either of these receptor subtypes, ATP is able to evoke an increase in intracellular Ca2+ ([Ca2+]i). [Ca2+]i has a key role in regulating the sensitivity of olfactory signal transduction. Odorants bind to specific receptors on olfactory receptor neurons (ORNs), thereby activating a G-protein coupled adenylyl cyclase/ cAMP second messenger cascade, leading to the sequential opening of cAMP-gated (CNG) cation channels and a large localized influx of [Ca2+]i. The increase in [Ca2+]i plays an important role as a third messenger in olfactory transduction. It opens Ca2+-activated Cl- channels, substantially amplifying the generator current. Calcium increases also mediate odor adaptation through modulation of CNG channel activity or of molecules in the transduction cascade. Thus, changes in [Ca2+]i homeostasis could alter the responsiveness of ORNs to stimuli. This application will test the general hypothesis that noxious or trigeminal nerve stimulation of the peripheral olfactory system evokes the release of ATP that modulates responsiveness of olfactory receptor neurons to odor. It will provide the first detailed molecular, pharmacological, electrophysiological, and immunofluorescence characterization of purinergic nucleotide receptors in peripheral mammalian olfactory structures and will distinguish the role of nucleotides in control, signaling, and modulation of olfaction. Because ATP is released during neurotransmission and by noxious stimuli, these studies may elucidate mechanisms for the observed reduction in olfactory sensitivity during exposure to noxious agents.