The roles and functions of olfactory transduction channels in the odorant response

嗅觉转导通道在气味反应中的作用和功能

• 批准号: 10187543
• 负责人: JOHANNES REISERT
• 金额: $ 34.95万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187543
• 关键词: Action Potentials; Address; Adenylate Cyclase; Affect; Afferent Neurons; Anions; Axon; Behavior; Behavioral; Binding; Brain; Cations; Cell membrane; Cells; Characteristics; Cholesterol; Cilia; Code; Coupled; Cyclic AMP; Cyclic Nucleotides; Electrophysiology (science); Environment; Event; Food; Friends; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Generations; Goals; Hair Cells; Ion Channel; Ion Channel Gating; Kinetics; Knock-out; Knockout Mice; Lead; Light; Lipids; Mediating; Membrane; Modeling; Molecular; Mucous Membrane; Mucous body substance; Nasal cavity; Neurons; Nose; Odorant Receptors; Odors; Olfactory Receptor Neurons; Partner in relationship; Perception; Peripheral; Photoreceptors; Physiological; Physiology; Play; Process; Property; Proteins; Receptor Cell; Regulation; Reporting; Research; Role; Sensory; Shapes; Signal Transduction; Smell Perception; Stimulus; System; Thinness; Vertebrates; Work; base; cyclic-nucleotide gated ion channels; insight; neglect; novel; olfactory bulb; receptor; response; sensory system; voltage

Summary Our senses convert environmental stimuli into electrical signals that are ultimately interpreted by the brain to guide our behavioral decisions. The conversion of stimuli relies on the ion channels expressed in sensory cells, and their properties thus determine how we perceive our environment. Olfactory receptor neurons (ORNs) in the nasal cavity recognize odorants and, unlike other sensory neurons such as photoreceptors and hair cells, are in direct contact with the external environment, protected only by a thin mucus layer. Olfactory cilia, the cellular compartment that contains the machinery that transduces odorants, must survive in this environment while remaining functional, adding extra demands on membrane integrity and function. The initial event of an odor molecule binding to an odorant receptor in the ciliary membrane leads, via activation of adenylyl cyclase, to opening of the olfactory cyclic-nucleotide gated (CNG) channel that allows Ca2+ influx, which in turn activates an excitatory Ca2+-activated Cl- channel, further depolarizing the neuron. This two-tiered sensory transduction mechanism based on one cationic and one anionic channels, is unique to ORNs and highly conserved across all vertebrates. Both the reason why ORNs use this two-stage ion channel system in general and why a combination of cation and anion conductances in particular is used to perceive odorants are unclear, as is the role of the Ca2+-activated Cl- channel. Only in 2009 was the molecular identity of the olfactory Ca2+-activated Cl- channel determined to be anoctamin 2 (Ano2), and despite a knockout model being available, the roles of Ano2, and therefore also of the CNG channel, remain unclear. We propose to use an Ano2-knockout mouse, electrophysiological and molecular approaches to define how these two ion channels shape the odorant-induced response. We will characterize which specific aspects of the response (adaptation, response reliability, action potential coding, etc.) are determined by a single ion channel or jointly by both. In addition, because the two channels must function in the constraints of the ciliary membrane, we will investigate how the channels rely on membrane constituents for their function and how altered membranes leads to detrimental olfactory function. By examining how the two-tiered sensory transduction mechanism of a cationic and an anionic ion channel operates seamlessly as a dual-component system, we will address fundamental questions in olfaction that have remained unanswered for the past 25 years. The long-term goal of this proposal is to establish how ORNs use their signal transduction in general and their ion channels in particular to reliably encode odorant stimuli, how transduction functions within the constraints of the ciliary membrane, and how this ultimately determines how odorants are perceived.

概括 我们的感官将环境刺激转化为最终由大脑解释的电信号 指导我们的行为决定。刺激的转化依赖于在感觉中表达的离子通道 细胞及其特性因此决定了我们如何看待环境。嗅觉受体神经元 （ORNS）在鼻腔中识别气味剂，并且与其他感觉神经元（例如感光体）和 毛细胞与外部环境直接接触，仅由薄粘液层保护。嗅觉 纤毛是包含传递气味剂的机械的细胞室，必须在此中生存 在保持功能的同时，对膜完整性和功能增加了额外的要求。 气味分子与睫状膜中的气味受体结合的初始事件导致 腺苷酸环化酶的激活，以开放嗅觉环核苷酸门（CNG）通道，该通道允许 Ca2+流入又激活了兴奋性Ca2+激活的Cl-通道，进一步使神经元去极化。 这种基于一个阳离子和一个阴离子通道的两层感觉转导机制是独一无二的 在所有脊椎动物中的ORN和高度保守。 Orns使用此两级离子频道的两个原因 通常，系统以及为什么阳离子和阴离子电导的组合被用来感知 气味尚不清楚，Ca2+活化的Cl-通道的作用也是如此。 仅在2009年才是嗅觉Ca2+活化的Cl-通道的分子身份 Anoctamin 2（ANO2），尽管有敲除模型，但ANO2的作用，因此也是 CNG通道，尚不清楚。我们建议使用ANO2敲除鼠标，电生理和 分子方法来定义这两个离子通道如何塑造气味诱导的反应。我们将 表征响应的哪些特定方面（适应性，响应可靠性，动作电位编码， 等）由单个离子通道或两者共同确定。另外，因为两个频道必须 在睫状膜的约束中的功能，我们将研究通道如何依赖膜 其功能的成分以及膜的改变如何导致有害的嗅觉功能。 通过检查阳离子和阴离子离子的两层感觉转导机制如何 渠道作为双重组件系统无缝运行，我们将解决嗅觉中的基本问题 在过去的25年中，这种情况一直尚未得到答复。 该提案的长期目标是确定ORN如何使用其信号转导的一般和 它们的离子通道特别是可靠地编码气味刺激，转导如何在 睫状膜的约束，以及如何最终决定了气味的感知。