Effects of chronic continuous hypoxia on the expression of SLC4A8 (NDCBE) in neonatal versus adult mouse brain

Abstract

Na-coupled HCO3 transporters (NCBTs) play important roles in brain pH regulation. One NCBT, the Na-driven Cl-HCO3 exchanger (SLC4A8 or NDCBE), appears to be the major regulator of intracellular pH (pHi), at least in some hippocampal pyramidal neurons. NDCBE is widely expressed throughout the central nervous system in rodent brain. In a previous study, it has been demonstrated that CCH decreases the abundance of NBCn1 and NBCn2 proteins in four regions of the mouse brain: cerebral cortex (CX), subcortex (SCX), cerebellum (CB), and hippocampus (HC). Here we report the effect of CCH (11% O2) on the expression of NDCBE protein in mouse brain. Neonates (beginning at age P2) or adult mice (beginning at P90) were subjected to either normoxia or CCH for durations of 14 or 28 days. Membrane-protein levels were assessed by western blotting using our polyclonal antibody directed against NDCBE. In neonates, CCH significantly decreased NDCBE expression in HC after 14 days and SCX after 28 days, but had no significant effect for other combinations of region/duration. In adults, however, CCH significantly decreased (by 20–50%) the expression of NDCBE in all four brain regions, both with 14 and 28 days’ duration. Thus, the mouse brain exhibits marked developmental differences in the response of NDCBE protein expression to CCH. We hypothesize that decreases in adult NDCBE protein levels, which are probably out of proportion to the decreases in other proteins, may be part of an adaptive response that reduces energy consumption and/or stabilizes brain pHi. The smaller or absent responses in the young animals could be related to neonatal hypoxia tolerance.

Cation‐Coupled Bicarbonate Transporters

“…In the brain, the NDCBE protein is localized to cell body membranes, cytosol, and processes of neurons (60, 179), thereby supporting the previous observations that the Na + -driven Cl,HCO 3 exchanger primarily governs HCO 3 − -dependent acid extrusion in neurons (22, 287). NDCBE is found in presynaptic nerve terminals, at the electron microscopic level (296), mostly in glutamatergic terminals and some GABAergic terminals (49).…”

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

“…This pattern is similar to the distribution of NBCn1 but different from that of NDCBE, which is most abundant in the subcortex compared with the other three tested regions (175). Within CA1-CA3 regions of the hippocampus, NBCn2 also exhibits an expression pattern complementary to that of NDCBE, inasmuch as NBCn2 expression is greatest in the CA3 region (429), whereas NDCBE expression appears to be strongest in the CA1 and CA2 regions (176).…”

“…Downregulation in hypoxia is also characteristic of NBCn1 and NDCBE, except that the downregulation of NDCBE occurs in adults but generally not in neonates (175).…”

“…Chronic continuous hypoxia (CCH) decreases the amount of NDCBE protein in the cortex, subcortex, hippocampus, and cerebellum of adult rat brains, but generally not in neonates (175). CCH also reduces the abundance of NBCn1 and NBCn2.…”

Structure, Function, and Trafficking of SLC4 and SLC26 Anion Transporters

“…SLC4A8 catalyzes the functional exchange of one extracellular sodium and two bicarbonates for one intracellular chloride (Grichtchenko et al, 2001;Romero et al, 2000). It is expressed in the brain and contributes to pH regulation in neurons and CSF secretion by the choroid plexus (Chen, Haddad, & Boron, 2008;Chen, Kelly, et al, 2008). Knockout mice exhibit neurological defects where SlcA8 is proposed to be a key regulator of presynaptic pH and modulator of glutamine release (Sinning et al, 2011).…”