Characterization of the brain-enriched Na+/H+ exchanger NHE5

脑富集 Na /H 交换器 NHE5 的表征

• 批准号: 371665-2009
• 负责人: Numata, Masayuki
• 金额: $ 2.7万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=483678
• 关键词: Characterization; brain; enriched; Na+; H+

Maintenance of the cellular acidity (pH) is important for most cell types as the majority of biochemical reactions and protein structures are tightly regulated by pH within the physiological range. This is especially the case with nerve cells (neurons) that conduct nerve impulses. In addition to the fundamental roles commonly observed in various cell types, highly localized and transient pH regulation mechanisms play crucial roles in modulating neuronal activities. For example, pH shifts modulate excitability because the function of many ion channels that are responsible for creating and conveying electric stimuli along the neuron is substantially influenced by changes in pH. Electric stimuli at the specialized structure located close to the adjacent neuron stimulate to release chemical substances called "neurotransmitters". This is sensed by "receptors" that bind to and react with the neurotransmitter. Release of neurotransmitters and recognition by the receptor allow neurons to transmit signals from one neuron to another. Neuronal pH regulates both release of neurotransmitters and proper function of receptors. Not surprisingly, neurons possess a number of sophisticated mechanisms to regulate cellular pH. Among them, Na+/H+ exchangers (NHEs), a group of ion transporters that exchange Na+ for H+ across membranes are proposed to be one of the most prominent players. This notion was strongly supported by the previous finding that genetic depletion of an NHE gene that is expressed in most cell types (NHE1) show brain damage leading to seizures and neuronal cell death. Interestingly, among nine additional NHEs that share similar structure and function, NHE5 is abundantly expressed in brain. Our research group has shown previously that NHE5 has a number of unique characters different from that of NHE1. The unique feature of NHE5 may account for novel roles in brain. We will test our hypothesis in which NHE5 regulates neuronal function and neuronal development by using various model cell systems. Our research will help advance basic knowledge in our understanding of pH regulation in neurons and aim to determine its impact on brain functions such as learning and memory.

维持细胞酸度 (pH) 对于大多数细胞类型都很重要，因为大多数生化反应和蛋白质结构都受到生理范围内 pH 的严格调节。 对于传导神经冲动的神经细胞（神经元）尤其如此。 除了在各种细胞类型中常见的基本作用外，高度局部化和瞬时的 pH 调节机制在调节神经元活动中也发挥着至关重要的作用。 例如，pH 值变化会调节兴奋性，因为许多负责沿着神经元产生和传递电刺激的离子通道的功能很大程度上受到 pH 值变化的影响。 对靠近相邻神经元的特殊结构进行电刺激会刺激释放称为“神经递质”的化学物质。 这是由与神经递质结合并发生反应的“受体”感知的。 神经递质的释放和受体的识别允许神经元将信号从一个神经元传递到另一个神经元。 神经元 pH 值调节神经递质的释放和受体的正常功能。 毫不奇怪，神经元拥有许多复杂的机制来调节细胞 pH 值。 其中，Na+/H+交换器（NHE）是一组跨膜将 Na+ 交换为 H+ 的离子转运蛋白，被认为是最重要的参与者之一。 这一观点得到了先前发现的有力支持，即大多数细胞类型（NHE1）中表达的 NHE 基因的基因缺失会导致脑损伤，导致癫痫发作和神经元细胞死亡。 有趣的是，在具有相似结构和功能的另外九个 NHE 中，NHE5 在大脑中大量表达。 我们的研究小组此前已表明NHE5具有许多不同于NHE1的独特特征。 NHE5 的独特特征可能解释了大脑中的新角色。 我们将通过使用各种模型细胞系统来检验我们的假设，即 NHE5 调节神经元功能和神经元发育。 我们的研究将有助于增进我们对神经元 pH 调节的理解，并旨在确定其对学习和记忆等大脑功能的影响。