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

细胞酸度（pH）的维持对大多数细胞类型都很重要，因为大多数生物化学反应和蛋白质结构都在生理范围内受到pH的严格调节。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普遍观察到的基本作用外，高度局部化和瞬时的pH调节机制在调节神经元活动中起着至关重要的作用。例如，pH值的变化可以调节兴奋性，因为负责沿神经元产生和传递电刺激的许多离子通道的功能受到pH值变化的实质性影响。位于邻近神经元附近的特殊结构的电刺激刺激释放称为“神经递质”的化学物质。这是由与神经递质结合并与之反应的“受体”感知的。神经递质的释放和受体的识别使神经元能够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，神经元具有许多复杂的机制来调节细胞ph。其中，Na+/H+交换器（NHEs），一组离子转运体，通过膜交换Na+为H+，被认为是最突出的参与者之一。这一观点得到了先前发现的有力支持，即在大多数细胞类型中表达的NHE基因（NHE1）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，在另外9种具有相似结构和功能的NHEs中，NHE5在大脑中大量表达。我们的研究小组先前已经表明，NHE5具有许多不同于NHE1的独特字符。NHE5的独特特征可能解释了它在大脑中的新作用。我们将通过使用各种模型细胞系统来验证NHE5调节神经元功能和神经元发育的假设。我们的研究将有助于提高我们对神经元pH调节的基本认识，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.