title: Variants of the electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse hippocampal neurons are regulated by extracellular pH changes: evidence for a Rab8a-dependent mechanism.
abstract: Changes in extracellular pH are common events in both pathological conditions and during normal brain function. In organs other than the brain, cells may respond to pH changes by trafficking of acid-base transporters. However, regulation of neuronal acid-base transporters during pH shifts is not understood. The aim of this study was to investigate regulatory mechanisms of the variants of the electrogenic sodium/bicarbonate cotransporter 1, NBCe1-A and NBCe1-B/C, in neurons following changes of extracellular pH. Therefore, primary mouse hippocampal neurons were exposed to extracellular acidosis or alkalosis. We show that acid-base changes regulated trafficking and membrane expression of neuronal NBCe1 but the underlying molecular cues were distinct for individual NBCe1 variants. Following extracellular acidosis NBCe1-A was recruited from intracellular pools to the plasma membrane, followed by increased membrane expression, whereas NBCe1-B/C was retrieved from the membrane. Extracellular alkalosis had no impact on NBCe1-A, but caused translocation of NBCe1-B/C toward the dendrites. We also show that acidosis-induced NBCe1-A, but not NBCe1-B/C, trafficking is mediated by Rab8a. Rab8a is expressed in hippocampal neurons, co-localizes, and interacts with NBCe1-A. Loss-of-function of Rab8a using specific siRNA prevented acidosis-induced redistribution of NBCe1-A. These data propose opposite recruitment pattern for NBCe1 variants in neurons following extracellular acid-base changes, implicating distinct physiological functions of individual NBCe1 variants, and introduce Rab8a as a novel molecular determinant and crucial mediator of acidosis-induced NBCe1 trafficking in neurons.
authors.affiliation: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Albert-Ludwigs University Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany. oliver.oehlke@anat.uni-freiburg.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Oehlke
authors.forename: Jan Manuel
authors.initials: JM
authors.lastname: Speer
authors.forename: Eleni
authors.initials: E
authors.lastname: Roussa
mesh_terms: D000138:Acidosis; D000471:Alkalosis; D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C546061:Rab8a protein, mouse; C498899:Slc4a4 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D020691:rab GTP-Binding Proteins