Regulation of V‐ATPase in mouse hippocampal neurons following metabolic‐induced‐ and activity‐dependent acid‐base changes

Abstract

Changes in extracellular pH (pHo) are common events associated with both physiological conditions and pathological states in brain function. Neuronal activity is associated with extracellular alkalinization and a rapid intracellular acidification whereas significant changes of pHo have also been observed during seizures and spreading depression. In the present study we have investigated regulation of V‐ATPase in hippocampal neurons following metabolic‐induced and activity‐dependent extracellular acid‐base changes. Therefore, dissociated primary hippocampal neurons and organotypic slice cultures have been used as experimental models in vitro. The results show differential regulation mechanisms of V‐ATPase depending on the cause of pathological stimulus. Metabolic acidosis caused translocation of V‐ATPase from intracellular pools towards the membrane, and increased V‐ATPase membrane expression. Acidosis‐induced V‐ATPase redistribution was mainly controlled by Rab11b, as assessed by loss‐of‐function experiments. In contrast, activity‐dependent acidosis resulted in both transcriptional and post‐translational V‐ATPase regulation in hippocampal neurons. The data suggest translolation of V‐ATPase as regulatory mechanism in neurons to cope with changes of pH and provide first evidence for a molecular mechanism underlying transporter trafficking in neurons.