DOPAMINERGIC MODULATION OF OLFACTORY SIGNAL TRANSDUCTION

嗅觉受体神经元（ORN）被赋予了令人难以置信的任务 区分超过 10,000 种气味分子。 ORN 不仅必须 破译气味的质量，它们还必须为大脑提供 强度信息。 最近的研究在这方面取得了长足的进展 识别和表征信号转导的组成部分 ORN 中的机械。气味与嗅觉纤毛上的受体蛋白结合 启动 G 蛋白介导的第二信使级联反应，导致 cAMP 或 IP3 短暂升高。两个第二信使门特定 睫状膜中的离子通道，导致产生 受体电位。嗅觉粘液提供周围感受器环境 其中化学气味信号转导的初始步骤 到电受体电位发生。外在自主和 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。抗氧化化学物质的存在 粘液表明粘液环境适合 神经递质的持久性以及这些神经递质的作用 不清楚。 ORN 对 cAMP 产生的气味的敏感性是 由受体蛋白的敏感性和 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 ORN 气味敏感性。潜在的调节位点包括受体 蛋白质、转导级联和效应通道。这方面的工作 该提案将检验神经递质多巴胺是的假设 存在于嗅觉粘液中，作用于 ORN 树突上的 D2 多巴胺受体 并通过改变基础水平来调节系统的灵敏度 cAMP 生产。我们的模型表明，多巴胺的存在 粘液受自主控制，并且增加或减少 多巴胺会增加或降低 ORN 的敏感性。这个型号 与三叉神经系统刺激减少的观察相符 青蛙的气味敏感性，以及气味的心理物理感知 暴露于有毒物质后强度降低（三叉神经 刺激）。 这些研究可能与以下疾病具有临床相关性： 多巴胺能通路受到干扰（帕金森病）并显示 嗅觉敏感性降低是早期症状。这方面的工作 该提案将确定多巴胺对 ORN 的调节作用，并将 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性降低。

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.