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

维持细胞的酸性(PH)对于大多数细胞类型是重要的，因为大多数生化反应和蛋白质结构在生理范围内受到pH的严格调控。对于传导神经冲动的神经细胞(神经元)来说尤其如此。除了在不同类型的细胞中普遍观察到的基本作用外，高度局部和瞬时的pH调节机制在调节神经元活动方面发挥着至关重要的作用。例如，pH变化调节兴奋性，因为许多负责沿神经元产生和传递电刺激的离子通道的功能在很大程度上受到pH变化的影响。位于邻近神经元附近的特殊结构上的电刺激刺激释放被称为“神经递质”的化学物质。这是由与神经递质结合并与之反应的“受体”感受到的。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的pH。其中，Na+/H+交换器(NHEs)是一组跨膜将Na+交换为H+的离子转运体，被认为是最重要的参与者之一。先前的发现有力地支持了这一观点，即在大多数细胞类型(NHE1)中表达的NHE基因的遗传缺失表明大脑损伤导致癫痫发作和神经细胞死亡。有趣的是，在另外9个结构和功能相似的NHEs中，NHE5在大脑中大量表达。我们的研究小组此前已经表明，NHE5具有许多与NHE1不同的独特特征。NHE5的独特功能可能解释了大脑中的新角色。我们将通过使用不同的模型细胞系统来验证我们的假设，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调节的基础知识，并旨在确定其对学习和记忆等大脑功能的影响。

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.