How the brain senses CO2

大脑如何感知二氧化碳

• 批准号: G1001259/1
• 负责人: Nicholas Dale
• 金额: $ 108.63万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1001259%2F1
• 关键词: How; brain; senses; CO2

Metabolism requires O2 and produces CO2 as a by-product. The amount of dissolved CO2 controls the acidity (pH) of our body fluids including blood. Many physiological processes are sensitive to pH, thus efficient control of the amount of dissolved CO2 in blood is a critical homoeostatic function. Special mechanisms exist to measure the amount of dissolved CO2 in blood ?if there is too much we breathe faster to drive off the excess, if there is too little we breathe less frequently. While there is evidence that CO2 is detected indirectly as pH, we have discovered a new molecular mechanism for the direct detection of CO2 ?CO2 binds to a type of channel called connexin 26 (Cx26), and in doing so causes it to open and release a chemical called ATP that activates neurons. Cx26 is sensitive to CO2 in exactly the physiological range required ?our normal levels of dissolved CO2 are at the mid-point of channel activation. Cx26 can thus respond to both increases and decreases in dissolved CO2. Cx26 is present in the correct areas of the brain to help control breathing. Our programme seeks to develop the genetic tools to analyze with great rigour the contributions of Cx26 to the measurement of CO2 and the control of breathing. Use of these tools will not only enable us to establish the causal link between Cx26 and behaviour, but also to determine the tissues, regions and cell types that are important for the detection of CO2. We also wish to understand the mechanism by which CO2 binds to the channel to change its conformation and cause it to open. We shall mix and match portions of CO2-sensitive and non-CO2-sensitive connexins to endow a previously non-sensitive connexin with CO2 sensitivity. This will tell us which part of the protein is important. We shall then identify the precise amino acid involved by mutating single amino acids in the critical region of the molecule. In parallel with this we shall use an analytical technique called NMR spectroscopy to directly and definitively test one possible way that CO2 could bind to the protein. Our proposal has the potential to transform understanding of how the brain senses CO2. This is likely to be important in understanding how CO2-sensing may be altered during pathologies such as congestive heart failure and chronic obstructive pulmonary disease.

新陈代谢需要O2，并产生CO2作为副产品。溶解的二氧化碳量控制着我们体液（包括血液）的酸度（pH值）。许多生理过程对pH值敏感，因此有效控制血液中溶解的CO2量是一种关键的稳态功能。存在特殊的机制来测量血液中溶解的CO2的量？如果太多，我们呼吸得更快，以赶走多余的，如果太少，我们呼吸得更少。虽然有证据表明，CO2是间接检测的pH值，我们已经发现了一种新的分子机制，直接检测CO2？二氧化碳与一种称为连接蛋白26（Cx26）的通道结合，这样做会导致它打开并释放一种名为ATP的化学物质，激活神经元。Cx26对CO2的敏感性正好在所需的生理范围内？我们正常的溶解二氧化碳水平处于通道激活的中点。因此，Cx26可以对溶解的CO2的增加和减少做出反应。Cx26存在于大脑的正确区域，以帮助控制呼吸。我们的计划旨在开发遗传工具，以严格分析Cx26对测量CO2和控制呼吸的贡献。使用这些工具不仅使我们能够建立Cx26和行为之间的因果关系，而且还可以确定对CO2检测重要的组织，区域和细胞类型。我们还希望了解CO2与通道结合以改变其构象并使其打开的机制。我们将混合和匹配部分的CO2敏感和非CO2敏感的连接蛋白，赋予以前不敏感的连接蛋白与CO2敏感性。这将告诉我们蛋白质的哪一部分是重要的。然后，我们将通过突变分子关键区域中的单个氨基酸来确定所涉及的精确氨基酸。与此同时，我们将使用一种称为NMR光谱的分析技术来直接和明确地测试CO2与蛋白质结合的一种可能方式。我们的提议有可能改变对大脑如何感知二氧化碳的理解。这对于理解在诸如充血性心力衰竭和慢性阻塞性肺病等病理过程中CO2传感如何改变可能是重要的。