The luminal pH of sorting endosomes is critical in determining the direction of the cargo and plays a crucial role in receptor desensitization, degradation and cell surface delivery of receptors upon ligand dissociation53. Early and recycling endosomes have more alkaline pH than late endosomes and lysosomes54. Alkalinization of the recycling pathway by elevated expression of NHE9 had the effect of increasing surface expression of the glutamate transporter GLAST and a consequent increase in glutamate uptake. Furthermore, this appears to be a general mechanism not specific for the astrocyte specific transporter, given the similar observations with transferrin receptor and uptake. By extension, impairment of NHE9 function in vivo may lead to hyperacidification of endosomal lumen, as observed in the yeast model and in cultured human glioma cells, which could result in lower levels of receptors and transporters at the synaptic membranes, and decreased of synaptic clearance of glutamate, consistent with etiology of epilepsy and autism.
