Department of Physiology, The Johns Hopkins University School of Medicine Baltimore, MD, USA.
Front Cell Neurosci. 2014 Jun 23;8:172. doi: 10.3389/fncel.2014.00172. eCollection 2014.
Autism imposes a major impediment to childhood development and a huge emotional and financial burden on society. In recent years, there has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na(+)/H(+) exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na(+), K(+)) content in early and recycling endosomal compartments. Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways. Two isoforms, NHE6 and NHE9 are highly expressed in brain, including hippocampus and cortex. Here, we summarize evidence for the importance of luminal cation content and pH on processing, delivery and fate of cargo. Drawing upon insights from model organisms and mammalian cells we show how eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters. These studies lead to cellular models of eNHE activity in pre- and post-synaptic neurons and astrocytes, where they could impact synapse development and plasticity. The study of eNHE has provided new insight on the mechanism of autism and other debilitating neurological disorders and opened up new possibilities for therapeutic intervention.
自闭症对儿童的发展造成了重大障碍，并给社会带来了巨大的情感和经济负担。近年来，有大量的遗传证据表明，eNHE（Na+/H+ 交换器的一个子集，定位于细胞内囊泡）与多种神经疾病有关，包括自闭症、注意力缺陷多动障碍（ADHD）、智力障碍和癫痫。eNHE 通过为 V-ATPase 泵出的质子提供渗漏途径，决定了腔室 pH 值，并调节早期和再循环内体区室中的阳离子（Na+、K+）含量。eNHE 的功能丧失突变导致内体腔室的过度酸化，这是由于泵和渗漏途径之间的失衡所致。两种同工型，NHE6 和 NHE9 在大脑中高度表达，包括海马体和皮层。在这里，我们总结了腔内阳离子含量和 pH 值对货物加工、运输和命运的重要性的证据。通过借鉴模式生物和哺乳动物细胞的研究成果，我们展示了 eNHE 如何影响膜受体和神经递质转运体的表面表达和功能。这些研究为前突触和后突触神经元和星形胶质细胞中的 eNHE 活性提供了细胞模型，它们可能影响突触的发育和可塑性。对 eNHE 的研究为自闭症和其他神经退行性疾病的发病机制提供了新的见解，并为治疗干预开辟了新的可能性。
