DOPAMINERGIC MODULATION OF OLFACTORY SIGNAL TRANSDUCTION

嗅觉感受器神经元(ONs)被赋予了这项不可思议的任务 区分了10,000多个气味分子。奥恩斯不仅必须 破译气味的质量，它们也必须为大脑提供 强度信息。最近的研究在以下方面取得了相当大的进展 识别和表征信号转导的组成部分 奥恩斯的机器。嗅觉纤毛上与受体蛋白结合的气味 启动G蛋白介导的第二信使级联反应，导致 一过性cAMP或IP3升高。两个第二信使都特定于门 睫状膜中的离子通道，导致产生 感受器潜力。嗅觉粘液提供感受器周围环境 其中化学气味信号转换的初始步骤 以产生电感受器的电势。外在自主神经和 三叉神经支配控制粘液分泌并可能释放 神经递质进入粘液。抗氧化剂在人体内的存在 粘液表明粘液环境对 神经递质的持久性，但这些神经递质的作用 都不清楚。Orns对营地产生的气味的敏感度是 由受体蛋白的敏感度和 环核苷酸门控(CNG)通道的敏感性。一种可能 释放到嗅觉粘液中的神经递质的作用是调节 嗅觉敏感度。潜在的调节位点包括受体 蛋白质、转导级联和效应器通道。这里面的工作 该提案将检验神经递质多巴胺是 存在于嗅觉粘液中，作用于ORN树突上的D2多巴胺受体 并通过改变基本电平来调节系统的灵敏度 夏令营制作。我们的模型表明，多巴胺在大脑中的存在 粘液在自主神经的控制下，在 多巴胺可增加或降低ONS的敏感性。这款车 与对三叉神经系统的刺激减少的观察相吻合 青蛙对气味的敏感性，以及对气味的心理物理感知 接触有毒物质后强度降低(三叉神经 刺激)。这些研究可能在临床上与以下疾病相关 多巴胺能通路受到干扰(帕金森氏症)，表现为 早期症状为嗅觉敏感度降低。这里面的工作 提案将确定多巴胺对Orns和Will的调节作用 提供有关外周多巴胺能通路如何参与的见解 与疾病相关的嗅觉敏感度降低。

Olfactory receptor neurons (ORNs) have been assigned the incredible task of distinguishing between over 10,000 odor molecules. Not only must ORNs decipher the quality of odors, they must also provide the brain with intensity information. Recent studies have made considerable progress in identifying and characterizing the components of signal transduction machinery in ORNs. Odors binding to receptor proteins on olfactory cilia initiate a G-protein-mediated second messenger cascade that results in the transient elevation of cAMP or IP3. Both second messengers gate specific ion channels in the ciliary membrane, resulting in the generation of receptor potentials. Olfactory mucus provides the perireceptor environment in which the initial steps of the transduction of a chemical odor signal to an electrical receptor potential occur. Extrinsic autonomic and trigeminal innervation controls mucus secretion and may release neurotransmitters into the mucus. The presence of antioxidant chemicals in the mucus suggests that the mucus environment is permissive for neurotransmitter persistence yet the actions of those neurotransmitters are unclear. The sensitivity of ORNs to cAMP-generating odors is determined by both the sensitivity of the receptor proteins and the sensitivity of the cyclic nucleotide gated (CNG) channel. One possible role for neurotransmitters released into olfactory mucus is to modulate ORNs odor sensitivity. Potential sites for modulation include the receptor proteins, transduction cascades, and effector channels. The work in this proposal will test the hypotheses that the neurotransmitter dopamine is present in olfactory mucus, acts on D2 dopamine receptors on ORN dendrites and modulates the sensitivity of the system by changing basal levels of cAMP production. Our model suggest that the presence of dopamine in the mucus is under autonomic control and that increases or decreases in dopamine would increase or decrease the sensitivity of ORNs. This model fits with observations that stimulation of the trigeminal system decreases odor sensitivity in frogs, and that the psychophysical perception of odor intensity decreases after exposure to noxious substances (trigeminal stimuli). These studies may be clinically relevant to diseases where dopaminergic pathways are disturbed (Parkinson's) and which display decreased olfactory sensitivity as an early symptom. The work in this proposal will determine the modulatory role of dopamine on ORNs and will provide insights into how peripheral dopaminergic pathways may be involved in disease-related reduced olfactory sensitivity.