Structural basis for sensory receptor function

感觉受体功能的结构基础

• 批准号: 10708084
• 负责人: Nicholas Bellono
• 金额: $ 59.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708084
• 关键词: Address; Ambush; Animal Behavior; Animals; Architecture; Behavior; Behavioral; Biochemistry; Biological; Biological Models; Biology; Biophysics; Brain; Cells; Cephalopoda; Characteristics; Chemicals; Comparative Biology; Complex; Cryoelectron Microscopy; Cuttlefish; Dependence; Detection; Disparate; Electrophysiology (science); Environment; Esthesia; Evolution; Exhibits; Family; Floor; Foundations; Goals; Homo; Human; Hydrophobicity; Investigation; Ion Channel; Ion Channel Gating; Ions; Life Style; Ligand Binding; Ligands; Mediating; Modification; Molecular; Molecular Conformation; Nervous System; Neurotransmitter Receptor; Neurotransmitters; Nicotinic Receptors; Octopus; Organ; Organism; Peripheral; Pharmacology; Physiological; Physiology; Predatory Behavior; Property; Protein Family; Proteins; Recombinants; Research; Resolution; Sampling; Sea; Sensory; Sensory Physiology; Sensory Receptors; Signal Transduction; Stimulus; Structure; System; Taste Perception; Terpenes; Testing; Touch sensation; Work; arm; biophysical analysis; biophysical properties; cell type; combinatorial; comparative; detection platform; experimental study; flexibility; marine; model organism; neurotransmission; novel; preference; receptor; receptor function; response; sensory system; structural biology; success; trait; voltage

PROJECT SUMMARY This proposal leverages cephalopods as a uniquely suited model system to ask how sensory systems detect and discriminate diverse environmental signals. Octopuses, as representative cephalopods, use their flexible arms and semi-autonomous distributed nervous system to explore their surroundings at a distance by locally detecting and capturing prey. This unique “taste by touch” system is mediated by chemotactile receptors (CRs), which are structurally similar to nicotinic acetylcholine receptors, but are insensitive to neurotransmitters, and instead detect poorly soluble molecules to mediate contact-dependent aquatic sensation. Here, we will exploit cephalopod chemotactile systems to understand how subtle evolutionary modifications in single proteins facilitate a functional transition from neuronal signaling to environmental sensation. Our approach spans structural biology to animal behavior. First, in Aim 1, we propose to determine high resolution structures of ligand- bound and apo octopus CRs to analyze structural and biophysical underpinnings of sensory versus neurotransmitter receptor function. In Aim 2, we will extend our comparative approach to CRs in distinct cephalopods with specific behaviors. In contrast to octopuses that use arms for active exploration, cuttlefish are ambush predators that strike and capture unsuspecting prey with their eight arms and two long tentacles. We recently discovered CRs in cuttlefish, which detect distinct ligands, exhibit different voltage dependence, and enable unique behaviors. Here, we will extend our analyses to include structurally informed experiments to compare aspects of ligand binding, ion permeation, and channel gating to ask how receptor function is suited to particular organismal behaviors. Finally, we recently found that octopus sensory cells express diverse CR subunit combinations that can form homo- and heteropentameric ion channel complexes. Subunit composition alters ligand sensitivity and ion permeation to tune signal detection, transduction, and filtering to influence peripheral processing in the octopus’ unusual distributed nervous system. In Aim 3, we will analyze the structural basis by which heteromeric complexes alter biophysical properties of ligand binding, ion permeation, and channel gating. Collectively, these studies will reveal broad principles underlying the structural basis for sensory receptor function and the evolution of biological novelty.

项目摘要 这个建议利用头足类动物作为一个独特的适合模型系统，问感觉系统如何检测 并区分不同的环境信号。章鱼作为头足类动物的代表，利用其灵活的 手臂和半自主分布式神经系统，以探索他们的周围环境的距离， 探测和捕获猎物这种独特的“触觉味觉”系统是由化学感受器（CR）介导的， 其在结构上类似于烟碱乙酰胆碱受体，但对神经递质不敏感， 而是检测到难溶性分子来调节接触依赖性水生感觉。在这里，我们将利用 头足类动物的化学触觉系统，以了解如何微妙的进化修改，在单一的蛋白质 促进从神经元信号传导到环境感觉的功能转变。我们的方法涵盖 从结构生物学到动物行为首先，在目标1中，我们提出确定配体的高分辨率结构- 结合和apo章鱼CRs来分析感觉与 神经递质受体功能在目标2中，我们将把我们的比较方法扩展到不同的CR， 有特殊行为的头足类动物。与使用手臂进行主动探索的章鱼不同，乌贼 用八只手臂和两条长长的触须袭击并捕捉毫无戒心的猎物的伏击掠食者。我们 最近在乌贼中发现的CRs，检测不同的配体，表现出不同的电压依赖性， 实现独特的行为。在这里，我们将扩展我们的分析，包括结构知情的实验， 比较配体结合、离子渗透和通道门控方面，以询问受体功能如何适合于 特殊的生物行为。最后，我们最近发现章鱼感觉细胞表达不同的CR亚基， 可以形成同源和异源五聚体离子通道复合物的组合。亚基组成改变 配体敏感性和离子渗透，以调节信号检测、转导和过滤，从而影响外周 在章鱼不同寻常的神经系统中进行处理。在目标3中，我们将分析结构基础， 所述异聚复合物改变配体结合、离子渗透和通道门控的生物物理性质。 总的来说，这些研究将揭示感觉受体功能结构基础的广泛原则 和生物学新奇性的进化。