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: 9596131
• 负责人: JOHANNES REISERT
• 金额: $ 34.92万
• 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/9596131
• 关键词: Action Potentials; Address; Adenylate Cyclase; Affect; Afferent Neurons; Anions; 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; Gated Ion Channel; 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电信号，最终由大脑解释 来指导我们的行为决策。刺激的转换依赖于感觉表达的离子通道 因此，细胞及其特性决定了我们如何感知环境。嗅觉受体神经元 鼻腔中的 ORN（ORN）可以识别气味，并且与其他感觉神经元（例如光感受器和 毛细胞直接与外部环境接触，仅由薄薄的粘液层保护。嗅觉 纤毛是包含传递气味的机制的细胞区室，必须在这种环境中生存 环境，同时保持功能，增加了对膜完整性和功能的额外要求。 气味分子与睫状膜中的气味受体结合的初始事件通过 激活腺苷酸环化酶，打开嗅觉环核苷酸门控 (CNG) 通道，从而允许 Ca2+ 流入，进而激活兴奋性 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通道和一个阴离子通道的两层感觉转导机制是独特的 ORN 在所有脊椎动物中高度保守。这就是 ORN 使用这种两级离子通道的原因 一般系统以及为什么特别使用阳离子和阴离子电导的组合来感知 气味剂以及 Ca2+ 激活的 Cl- 通道的作用尚不清楚。 直到 2009 年，嗅觉 Ca2+ 激活的 Cl- 通道的分子特性才被确定为 anoctamin 2 (Ano2)，尽管存在敲除模型，但 Ano2 的作用以及因此也 CNG渠道仍不清楚。我们建议使用 Ano2 敲除小鼠，进行电生理学和 分子方法来定义这两个离子通道如何塑造气味引起的反应。我们将 描述反应的具体方面（适应、反应可靠性、动作电位编码、 等）由单个离子通道或两者共同确定。此外，由于两个通道必须 在睫状膜的约束下发挥作用，我们将研究通道如何依赖于膜 其功能的组成部分以及膜的改变如何导致有害的嗅觉功能。 通过研究阳离子和阴离子的两层感觉传导机制 通道作为双组件系统无缝运行，我们将解决嗅觉中的基本问题 过去25年来这些问题一直没有得到解答。 该提案的长期目标是确定 ORN 如何在一般情况下使用其信号转导 它们的离子通道特别是可靠地编码气味刺激，转导如何在 睫状膜的限制，以及这最终如何决定气味剂的感知方式。