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

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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.