Regulation of Olfactory Signal Transduction

描述（由申请人提供）：本研究的长期目标是阐明感官知觉的分子机制。具体来说，我们在本提案中寻求了解Ca2+反馈机制如何调节嗅觉感觉神经元（OSN）在体内的功能，以及这些机制如何促进动物检测和辨别气味的能力。Ca2+通过钙调蛋白（calmodulin, CaM）调节几种信号转导蛋白，在OSN响应的调节中起核心作用。先前的体外研究表明嗅觉环核苷酸门控（CNG）通道和磷酸二酯酶1C （PDE1C）是Ca2+/CaM的主要靶点。然而，这些Ca2+/ cam靶点相互作用在OSN生理和嗅觉行为中的功能意义尚未确定。我们正在利用分子遗传学特异性地消除CNG通道和PDE1C中的Ca2+/CaM结合位点。这种方法可以系统地分析Ca2+/CaM在调节OSN生理和最终嗅觉行为中的作用。在具体目标1中，我们将确定CNG通道中单个CaM结合域对Ca2+/CaM对OSN响应的调节的贡献。Specific Aim 2旨在描述PDE1C的基础活性和Ca2+/ cam刺激活性如何独立调节OSN反应。在具体目标3中，我们将研究OSN生理调节如何帮助嗅觉行为，如气味跟踪和辨别。提出的实验将有助于更好地理解信号转导蛋白的调节与OSN生理学和嗅觉行为的联系。这些知识将进一步加深我们对正常嗅觉功能和嗅觉功能障碍的理解，并将深入了解所有感觉系统的共同原理。这项研究旨在了解嗅觉检测细胞中关键蛋白质的调节如何影响嗅觉。从这些研究中获得的知识将增加我们对嗅觉系统正常功能和嗅觉功能障碍的理解。

DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate molecular mechanisms underlying sensory perception. Specifically, we seek in this proposal to understand how Ca2+ feedback mechanisms regulate olfactory sensory neuron (OSN) function in vivo and how these mechanisms contribute to the ability of the animal to detect and discriminate odors. Ca2+ plays a central role in regulating OSN responses by modulating several signal transduction proteins via calmodulin (CaM). Previous in vitro studies have implicated the olfactory cyclic nucleotide-gated (CNG) channel and phosphodiesterase 1C (PDE1C) as major targets of Ca2+/CaM. However, the functional significance of these Ca2+/CaM-target interactions in OSN physiology and olfactory behavior has not been determined. We are employing molecular genetics to specifically eliminate Ca2+/CaM binding sites in the CNG channel and PDE1C. This approach allows a systematic analysis of the role of Ca2+/CaM in regulating OSN physiology, and ultimately olfactory behavior. In Specific Aim 1 we will determine the contribution of individual CaM-binding domains of the CNG channel to Ca2+/CaM regulation of OSN responses. Specific Aim 2 seeks to delineate how the basal activity and Ca2+/CaM-stimulated activity of PDE1C independently regulate OSN responses. In Specific Aim 3, we will investigate how regulation of OSN physiology aids olfactory behaviors such as odor tracking and discrimination. The proposed experiments will lead to a better understanding of the connection from regulation of signal transduction proteins to OSN physiology, and to olfactory behavior. This knowledge will further our understanding of normal olfactory function and olfactory dysfunctions, and will provide insight into principles common to all sensory systems. This research aims to understand how regulation of key proteins in the odor-detecting cells influences the sense of smell. The knowledge from these studies will add to our understanding of both the normal function of the olfactory system and olfactory dysfunctions.