Structural basis for sensory receptor function

项目总结 这一建议利用头足类动物作为一个独特的模型系统来询问感官系统是如何检测到 并区分不同的环境信号。章鱼作为头足类的代表，使用其灵活的 手臂和半自主分布式神经系统，通过局部方式远程探索周围环境 探测和捕获猎物。这种独特的“触觉味觉”系统是由化学触觉受体(CRS)介导的， 在结构上与烟碱型乙酰胆碱受体相似，但对神经递质不敏感，以及 取而代之的是检测难于溶解的分子来调节接触依赖的水生感觉。在这里，我们将利用 头足类化学活动系统了解单个蛋白质中微妙的进化修饰 促进从神经元信号到环境感觉的功能转变。我们的方法跨越了 动物行为的结构生物学。首先，在目标1中，我们建议确定配体的高分辨结构- 绑定和脱脂章鱼CRS以分析感觉和生物物理基础与 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CRS 有特殊行为的头足类动物。与使用手臂进行积极探索的章鱼不同，乌贼 伏击用八只胳膊和两只长触须攻击并捕获毫无戒心的猎物的捕食者。我们 最近在墨鱼中发现的CRS，检测到不同的配体，表现出不同的电压依赖性，以及 启用独特的行为。在这里，我们将扩展我们的分析，将结构信息实验包括到 比较配体结合、离子渗透和通道门控等方面，询问受体功能如何适用于 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亚单位 可以形成同向和异向五元离子通道络合物的组合。亚基组成改变 配基灵敏度和离子渗透性，调整信号检测、转导和过滤以影响外周 在章鱼不同寻常的分布式神经系统中进行处理。在目标3中，我们将通过以下方式分析结构基础 这些异构体络合物改变了配体结合、离子渗透和通道门控的生物物理性质。 总的来说，这些研究将揭示感官感受器功能的结构基础背后的广泛原理 以及生物新颖性的进化。此外，头足类CRS与相关类群的比较 哺乳动物神经递质受体将定义核心通道结构，以洞察保守的 药理靶标。

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. Moreover, comparisons between cephalopod CRs and related mammalian neurotransmitter receptors will define core channel architecture for insights regarding conserved pharmacological targets.