How the brain senses CO2

新陈代谢需要氧气，并产生二氧化碳作为副产品。溶解的二氧化碳的量控制着包括血液在内的体液的酸度(PH)。许多生理过程对pH都很敏感，因此有效控制血液中溶解的二氧化碳的量是一项关键的稳态功能。有特殊的机制来测量血液中溶解的二氧化碳的量？如果太多，我们呼吸得更快，以消除多余的二氧化碳，如果太少，我们呼吸的频率就会降低。虽然有证据表明二氧化碳是作为pH被间接检测到的，但我们已经发现了一种直接检测二氧化碳的新的分子机制？二氧化碳与一种名为连接蛋白26(Cx26)的通道结合，并在这样做的过程中导致它打开并释放一种名为ATP的化学物质，激活神经元。Cx26在所需的生理范围内对二氧化碳非常敏感--我们的正常溶解二氧化碳水平处于通道激活的中点。因此，Cx26可以同时对溶解二氧化碳的增加和减少做出反应。Cx26存在于大脑中帮助控制呼吸的正确区域。我们的计划寻求开发基因工具，以非常严格地分析Cx26对二氧化碳测量和呼吸控制的贡献。使用这些工具不仅使我们能够建立Cx26和行为之间的因果联系，而且还可以确定对检测二氧化碳重要的组织、区域和细胞类型。我们还希望了解二氧化碳与通道结合以改变其构象并导致其开放的机制。我们将混合和匹配部分二氧化碳敏感和非二氧化碳敏感的连接蛋白，以赋予以前不敏感的连接蛋白二氧化碳敏感性。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，我们将使用一种名为核磁共振光谱学的分析技术来直接和明确地测试二氧化碳可能与蛋白质结合的一种方式。我们的提议有可能改变人们对大脑如何感知二氧化碳的理解。这可能对于理解二氧化碳感知在充血性心力衰竭和慢性阻塞性肺疾病等病理过程中可能发生的变化非常重要。

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.