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.

代谢需要O2并产生二氧化碳作为副产品。溶解的二氧化碳量控制了包括血液在内的体液的酸度（pH）。许多生理过程对pH值敏感，因此有效控制血液中溶解的二氧化碳量是关键的同抑制功能。存在特殊的机制来测量血液中溶解的二氧化碳量？如果我们呼吸太多以至于无法消除多余的二氧化碳，如果太少，我们呼吸频率较小。尽管有证据表明二氧化碳被间接检测为pH值，但我们发现了一种直接检测二氧化碳？二氧化碳的新分子机制，该机制与一种称为连接蛋白26（CX26）的通道结合，并导致其打开并释放一种称为ATP的化学物质，可激活神经元。 CX26正好在所需的生理范围内对CO2敏感？我们的正常溶解CO2水平处于通道激活的中点。因此，CX26可以响应溶解的CO2的增加和减少。 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，以严格地分析CX26对CO2测量和呼吸控制的贡献。这些工具的使用不仅将使我们能够在CX26和行为之间建立因果关系，还可以确定对检测CO2很重要的组织，区域和细胞类型。我们还希望了解二氧化碳与通道改变其构象并导致其打开的机制。我们将混合和匹配对CO2敏感和非CO2敏感的连接素的部分，以赋予先前非敏感的连接蛋白具有CO2敏感性。这将告诉我们蛋白质的哪一部分很重要。然后，我们将通过突变分子临界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，我们将使用称为NMR光谱的分析技术直接，确定地测试CO2可以与蛋白质结合的一种可能的方法。我们的建议有可能改变对大脑感知二氧化碳的理解。这对于理解在充血性心力衰竭和慢性阻塞性肺部疾病等病理期间如何改变二氧化碳感应可能很重要。