BPB Reports

Paper Details

BPB Reports
Vol. 2 No. 1 p.7-18 2019
Regular Article
Calcineurin Binds to a Unique C-Terminal Region of NBCe1-C, the Brain Isoform of NBCe1 and Enhances its Surface Expression
  • Akihiro Mizutani (Department of Pharmacotherapeutics, Showa Pharmaceutical University / mizutani@ac.shoyaku.ac.jp)
Naomi Hasegawa 1) , Naoya Hatano 2) , Suguru Tohyama 1) , Sayaka Kita 1) , Katsuhiko Mikoshiba 3) , Akihiro Mizutani 1)
1) Department of Pharmacotherapeutics, Showa Pharmaceutical University , 2) Division of Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University , 3) Laboratory for Developmental Neurobiology, Brain Science Center, RIKEN
Received: February 13, 2019;   Accepted: February 13, 2019;   Released: March 06, 2019
Keywords: NBCe1, calcineurin, astrocytic pH regulation, synaptic cleft

NBCe1 (electrogenic Na+/HCO3 – cotransporter 1) is a product of gene SLC4A4 and has five splice variants, NBCe1-A through NBCe1-E. In agreement with an essential role of NBCe1 in cellular pH regulation, human families carrying missense mutations of gene SLC4A4 show proximal renal tubular acidosis. Some of them exhibit brain function-related symptoms, such as migraine and mental retardation, but physiological roles of NBCe1 in brain function remain unclear. To gain insights into NBCe1-specific functions in the brain, we herein identified proteins that specifically bind to a unique C-terminal region of NBCe1-C, a brain-specific NBCe1 isoform. We found that a catalytic subunit of calcineurin binds to the C terminus of NBCe1-C in the mouse cerebellum. Heterologous-coexpression experiments revealed that calcineurin binds to NBCe1-C via a “PQIRIE” motif at its C terminus. The interaction enhanced cell surface expression of NBCe1-C, resulting in an increase of its transporter activity, for which the phosphatase activity of calcineurin was essential. When NBCe1-C was stably expressed in HeLa cells, its cell surface expression was enhanced by an intracellular Ca2+ concentration increase and was suppressed by FK506, a specific inhibitor of calcineurin. These mechanisms of surface expression and transport activity of NBCe1-C regulated by the Ca2+–calcineurin axis indicate specialized functions of NBCe1-C in the brain.