Purinergic Receptors in Olfactory System

描述(申请人提供)：最近的证据表明 胞外ATP在细胞信号转导中起重要作用，可以作为一种 感觉系统中的神经调节剂。有害刺激，细胞损伤和某些 病理生理条件可引起胞浆ATP的释放。ATP可以绑定 两种嘌呤能受体中的任何一种：P2Y G蛋白偶联受体或P2X 离子通道形成受体。通过这两种受体亚型中的任何一种，ATP都是 能引起细胞内钙离子([Ca~(2+)]i)升高。[CA2+]我有钥匙 在调节嗅觉信号转导敏感性中的作用。香体剂 与嗅觉感受器神经元上的特定受体结合，从而 激活G蛋白偶联的腺酰环化酶/cAMP第二信使级联， 导致cAMP门控(CNG)阳离子通道的顺序开放和 大量的局部[Ca~(2+)]i内流。[Ca~(2+)]i的升高在 在嗅觉传导中扮演第三信使的角色。它打开了钙激活的氯- 通道，大大放大了发电机电流。钙也会增加 通过调节CNG通道活动或 转导过程中的分子级联。因此，[Ca~(2+)]i动态平衡的变化 可以改变Orns对刺激的反应。此应用程序将测试 一般假设是伤害性刺激或三叉神经刺激 外周嗅觉系统唤起调节ATP的释放 嗅觉感受器神经元对气味的反应性。它将提供第一个 详细的分子、药理、电生理和 人脑组织中嘌呤能核苷酸受体的免疫荧光特性 外周哺乳动物的嗅觉结构，并将其作用区分开来 核苷酸在控制、信号和调节嗅觉中的作用。因为ATP是 在神经传递和有害刺激下释放，这些研究可能 阐明观察到的嗅觉敏感度下降的机制 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.