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The choroid plexus sodium‐bicarbonate cotransporter NBCe2 regulates cerebrospinal fluid pH
Author(s) -
Barbuskaite Dagne,
Praetorius Jeppe,
Christensen Henriette L,
Rojek Alexandra,
Nielsen Hans Malte,
Fuchtbauer ErnstMartin,
Wang Tobias,
Damkier Helle Hasager
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.702.4
Subject(s) - intracellular ph , choroid plexus , chemistry , acidosis , bicarbonate , endocrinology , medicine , cotransporter , acid–base homeostasis , homeostasis , dids , intracellular , biochemistry , sodium , biology , central nervous system , organic chemistry , membrane
Respiratory centers in the central nervous system (CNS) react to changes in pCO 2 and maintain systemic acid/base homeostasis by controlling the rate and depth of respiration. Both blood‐brain barrier and blood‐CSF barrier are highly permeable to CO 2 enabling swift transmission of arterial pCO 2 fluctuations to be coupled with CSF pH changes, whilst both barriers are much less permeable to H + and HCO 3 − , hence masking the effects of metabolic acid‐base disturbances. The electrogenic Na + ‐HCO 3 − cotransporter NBCe2 is expressed in the CSF‐facing plasma membrane of the choroid plexus epithelial (CPE) cells and could be a regulator of CSF pH. We hypothesized that NBCe2 is responsible for HCO − extrusion into the ventricle lumen to counteract decreases in CSF pH during acidosis. Intracellular pH (pH i ) measurements on CPE cells from NBCe2 knockout (KO) mice showed a statistically significant 84% increase in Na + ‐dependent acid extrusion following intracellular acidification by ammonium chloride prepulse and an 81% reduction in DIDS‐sensitive base efflux after intracellular alkalization by trimethylamine. Knockout of NBCe2 abolished CSF pH recovery from hypercapnia‐induced acidosis compared to control mice: wt (n=5): 0.0048 ± 0.003 vs ko (n=6): −0.0001±0.0002 pH units/min, p=0.0043. Choroid plexus targeted NBCe2 knockdown mice generated by intracerebroventricular installation of siRNA revealed a similar effect: Control (n=5): 0.002+/−0.0004 vs. NBCe2 knockdown (n=7): −0.0001±0.0007, p=0.047. Knockout of NBCe2 did not affect respiration rate or tidal volume compared to wildtype, and revealed a similar ventilatory response as controls when exposed to 5% CO 2 . In conclusion, we show that NBCe2 is important for recovery of CSF pH after CO 2 induced acidosis by transporting HCO 3 − into the CSF. This suggests a significant role for NBCe2 in regulating brain pH when faced with an acid challenge independent of the respiratory response. Support or Funding Information Dagne Barbuskaite is funded by a PhD stipend from the Faculty of Health and Medical Sciences and the department of Cellular and Molecular Medicine, Copenhagen University. Henriette L. Christensen is funded by a PhD stipend from the Faculty of Health, Aarhus University. The project is financed by the Danish Council for Independent Research/Medical sciences and the Laege Sofus Carl Emil Friis og Olga Doris Friis' legat.