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Bicarbonate Transport in Health and Disease
Bicarbonate Transport in Health and Disease
Abstract
Bicarbonate (HCO32) has a central place in human physiology channels and ZIP metal transporters contribute to bicarbonate
as the waste product of mitochondrial energy production and movement across membranes. Defective bicarbonate transport
for its role in pH buffering throughout the body. Because leads to diseases, including systemic acidosis, brain dysfunc-
bicarbonate is impermeable to membranes, bicarbonate trans- tion, kidney stones, and hypertension. Altered expression lev-
port proteins are necessary to enable control of bicarbonate els of bicarbonate transporters in patients with breast, colon,
levels across membranes. In humans, 14 bicarbonate transport and lung cancer suggest an important role of these transport-
proteins, members of the SLC4 and SLC26 families, function ers in cancer. V
C 2014 IUBMB Life, 66(9):596–615, 2014
life span of cells (79), arising from the domain’s ability to asso-
ciate with the cytoskeleton and glycolytic enzymes (80–82).
In addition to erythrocyte AE1 (eAE1), kAE1 (an N-
terminal truncated version of eAE1 transcribed from an alter- Pancreatic bicarbonate secretion. Pancreatic fluid has
nate promoter lacking the first 65 amino acids) is expressed in FIG 3 the highest HCO32 concentration of any bodily fluid,
the basolateral membrane of a-intercalated cells of the renal about 140 mM (65). To achieve this transepithelial
collecting duct (Fig. 4; refs. 6 and 83). In the basolateral mem- flux, the cell is loaded with HCO32 by NBCe1 and by
brane, kAE1 transports HCO32 from the cytosol to the blood, diffusion of CO2 into the cell, followed by CAII-
mediated catalysis to HCO32 and H1. NHE1 removes
thus contributing to renal acid secretion. H1 and loads the cell with additional Na1. Patients
AE1 Structure. High-sequence identity between membrane with cystic fibrosis have defective pancreatic HCO32
domains of AE1 and other members of the SLC4 family (30– secretion, indicating a key role of CFTR in pancreatic
HCO32 secretion. The role of CFTR is twofold: 1)
45% identity and 37–54% similarity) suggests that SLC4 mem- CFTR is a Cl2 channel, providing extracellular Cl2 to
brane domains share a common folded structure. Thus, AE1 sustain Cl2/HCO32 exchange by SLC26A6, and 2)
provides the best insight into the structure of all SLC4 proteins. CFTR is a HCO32 channel, mediating HCO32 efflux.
Studies of AE1 topology and cryo-electron microscopy have Not shown in this simplified model are the ion chan-
provided low-resolution structures for the membrane domain nels/Na1/K1-ATPase required to maintain homeosta-
sis. NBCn1 localizes to the apical membrane, but
(84–87). Human AE1 is composed of two domains: an N- functions in HCO32 salvage, not secretion (65). The
terminal cytoplasmic domain and a C-terminal membrane mechanism of pancreatic duct cell HCO32 secretion
domain with a short C-terminal cytoplasmic region. has been thoroughly reviewed (65).
Topology model for AE1 on the basis of ClC homology. Topology model for human AE1 (88) developed by structural homology
FIG 5 modeling to the ClC crystal structure (89). Boxes with letters represent the structural elements designated in the ClC crystal
structure. Branched structure represents the position of N-linked glycosylation at N642. Numbers represent the amino acid
numbers. N and C termini are labeled, and the missing N-terminal cytoplasmic domain is marked by dots.
examples of AE2 function, in acid-secreting osteoclasts and tured cardiomyocytes from ae32/2 mice are less responsive to
gastric parietal cells, AE2 basolateral Cl2/HCO32 exchange stimuli that induce hypertrophic growth than wild-type coun-
loads the cell with Cl2 and prevents cytosolic alkalosis that terparts (127). Further roles for AE3 in the heart came from
would otherwise arise on HCl secretion (Fig. 6). AE2 regulates the study of ae32/2 mice crossed with tropomyosin-mutant
cytosolic pH and is thus steeply negatively regulated at acidic (TM180) mice, which suggested that loss of AE3 was not cardi-
cytosolic pH (112). AE2-mediated regulatory cell volume oprotective against hypertrophic growth (128). The discrepant
increase (115) coordinates action of AE2 with a Na1/H1 effects of AE3 in cardiac hypertrophic growth may arise from
exchanger, resulting in cytosolic NaCl loading, without pH differences in genetic background of the mouse strains. Alter-
change, and osmotic fluid movement in the cell (116). natively, the observation of protective effects of AE3 ablation
was made in cultured isolated cardiomyocytes (127), whereas
AE2 in Disease. Ae22/2 mice manifest growth retardation,
a protective role of AE3 expression was found in the studies of
failure of tooth eruption, and gastric achlorhydria, as well as
intact hearts (128). Careful studies of ae32/2 mice suggested
mild gastric dysplasia, reflecting the critical role played by AE2
that ae32/2 hearts responded to stress in a way similar to
in acid loading in parietal cells (117). Loss of AE2 function in
hearts in failure, suggesting a key protective role of AE3 (129).
these mice was lethal to the embryo and most died around the
Indeed, one report found that an inhibitory anti-AE3 antibody
time of weaning. AE2 and NBCe1, expressed on apical and
impaired recovery from alkaline load and in the response of
basolateral membrane of secretory ameloblasts, respectively
cardiac myocytes to endothelin stimulation (130).
(118), have important roles in tooth development (119). The
key role of AE2 in acid secretion by bone-resorbing osteoclasts
(Fig. 6) means that loss of AE2 shifts bone balance toward Na1/Bicarbonate Cotransporters of the SLC4 Family
osteopetrosis or pathologically high bone density. Na1/Bicarbonate Cotransporters (NBCs) cluster separately
from AE proteins phylogenetically (Fig. 2) and further divide
AE3 (SLC4A3). AE3 is comparable with AE2, in having a lon- into electrogenic NBCs (NBCe1 and NBCe2) and electroneutral
ger cytoplasmic N-terminal region than AE1 and pH sensitivity NBCs (NBCn1, NBCn2, and NDCBE). The stoichiometry of
of transport activity (113). Two alternate transcripts, bAE3 cotransport for both NBCe1 and NBCe2 is 1 Na1:2 HCO32/1
(brain AE3, also called full length AE3) and cAE3 (cardiac Na1:3 HCO32 influx or efflux depending on the tissue distribu-
AE3), are transcribed from alternative promoters (120,121). tion, [Ca21], and phosphorylation status of the protein
AE3 is commonly referred to as the anion exchanger of excita- (131–133). A number of transport models have been proposed
ble tissue as its distribution is limited to brain (bAE3), retina for NBCe1; however, no particular model can be assigned yet
(bAE3 and cAE3), and cardiac tissues (cAE3). (see ref. 134). The substrate that NBCs transport is under dis-
cussion. Some data suggest that NBCe1 can carry CO322
AE3 in Disease. The AE3-A867D variant has been found in
instead of 2 HCO32 (135,136). The physiological significance of
some patients with idiopathic generalized epilepsy (122). Hetero-
CO322 transport, however, remains unclear as CO322 levels
logously expressed AE3-A867D had reduced functional activity
are much lower than HCO32 in blood. In blood at pH 7.4,
and processed normally to the cell surface. This AE3 variant
[HCO32] (pKa 6.4) is about 1,000-fold higher than [CO322] (pKa
was thus suggested to promote epilepsy through alterations of
10.3).
brain cell volume and pH homeostasis (123). Additionally, these
effects may be mediated through alterations of intracellular Cl2 NBCe1 (SLC4A4). The first NBC identified was NBCe1 (e, for
concentrations, which would impact on the activity of GABA Cl2 electrogenic and number for order of identification), cloned
channels, affecting neurotransmission. Consistent with a role in from salamander kidney (13), which led to the identification of
epilepsy etiology, ae32/2 mice have a reduced threshold for the human ortholog (14,137). NBCe1 has two domains: a cyto-
chemically induced seizure (124). plasmic N-terminal domain and a 14-transmembrane segment
The retina is the most metabolically active tissue of the membrane domain, with a cytoplasmic C-terminal tail
human body, and AE3 has an important role in disposal of (138,139). Interestingly, the cytoplasmic domain of NBCe1 has
metabolic waste HCO32 (pKa of the conversion of mitochon- residues critical for substrate bicarbonate entry into the mem-
drial respiratory waste product CO2 to HCO32 1 H1 is near the brane domain (140), a feature that is not found in AE1 (141),
cytosolic pH, leading to the accumulation of significant level of despite sequence conservation between the domains of the two
bicarbonate; Fig. 1). Indeed, ae32/2 mice can manifest visual proteins. NBCe1 is dimeric with each subunit functioning inde-
defects, arising from loss of AE3 from the inner retina (125). pendently in transport activity (142). The site of highest
Significant roles have been assigned to AE3 in the heart. NBCe1-a expression is basolateral membrane of proximal
In heart failure, cardiac hypertrophy (increased cell size with- tubule, where it is plays a critical role in reabsorption of
out increased cell number) is a central feature. Pathological HCO32 base into the blood (Fig. 7; ref. 143). NBCe1-b (N-termi-
concerted action of NHE1 and AE3 has been proposed to cause nal 41 amino acids of NBCe1-a are replaced by 85 amino
cell loading with NaCl, leading to hypertrophic growth, in part acids) is widely expressed in basolateral membrane of pan-
through an inhibitory effect on the plasma membrane Na1/ creas (144,145), where it facilitates efflux of HCO32 into the
Ca21 exchanger, NCX1 (126). Consistent with this idea, cul- pancreatic duct (Fig. 3; ref. 146). NBCe1-c (46 amino acid of Ct
combined auditory/visual defects in nbcn12/2 mice are similar suggesting that the protein functions as a Na1-coupled trans-
to Usher syndrome, the most common deafness/blindness syn- porter. Yet, SLC4A9 cloned from the rabbit kidney (27) and rat
drome in humans. Physical interactions between NBCn1 and (181) displayed Cl2/HCO32 exchange activity when expressed
proteins defective in Usher syndrome, including the scaffold in HEK293 cells, leading to the name AE4. One preliminary
protein Harmonin, led to the suggestion that NBCn1 is a key report found that AE4 is an electroneutral Na1-coupled bicar-
component of a coordinated protein complex critical to control bonate cotransporter (28), which would be consistent with the
of retinal and inner ear function (172). protein’s phylogeny. Localization of SLC4A9 to the basolateral
A role of NBCn1 in control of vascular tone is also strongly membrane of b-intercalated cells of the rabbit cortical collect-
indicated. nbcn12/2 mice are mildly hypertensive, and these ing duct, combined with reduced expression during acidosis,
mice show decreased responsiveness to the vasodilator, nitric are consistent with a role of the protein in efflux of Na1/
oxide (173). Studies of these mice indicate an important role of HCO32 from cytosol into blood (182).
NBCn1 in the regulation of vascular cytosolic pH.
SLC4A9 in Disease. Slc4a92/2 mice have no obvious phe-
NBCn2 (SLC4A10). NBCn2 (previously referred to as NCBE, for notype, suggesting that the role of SLC4A9 is dispensable or
Na1-dependent Cl2/Bicarbonate exchanger), primarily expressed can be compensated by other genes (183).
in brain, differs from NBCn1 functionally as it can carry out two Bicarbonate Transporters of the SLC26 Family
uncoupled transport activities: 1) Cl2 self-exchange in 1:1 ratio SLC26 family members function as Na1-independent electro-
(stimulated by HCO32), and 2) cotransport of 1 Na1 and 1 HCO32 neutral/electrogenic anion exchangers or as anion channels,
(30). NBCn2 also facilitates Na1-dependent Cl2/HCO32 exchange with broad substrate range, distinguishing them from the
(30,174). SLC4 family of bicarbonate transporters. Important physiologi-
NBCn2 in Disease. Localization of NBCn2 to the basolateral cal roles of this group of transporters are evident from its dis-
surface of the choroid plexus epithelium, combined with the tinct distribution pattern and link to various disease states, as
small brain ventricles in slc4a102/2 mice, strongly suggest a cen- described below. Of the 11 SLC26 genes, SLC26A10 is a pseu-
tral role of NBCn2 in CSF production (160,175). Protection dogene, and only SLC26A3, 4, 6, 7, and 9 gene product trans-
against serious epileptic seizures in the slc4a102/2 mice, expres- port bicarbonate (Table 1).
sion of NBCn2 in hippocampal neurons, and significant decrease
in recovery from acid load also indicate a key role of NBCn2 in Structure of SLC26 Proteins
homeostatic control of neuronal pH (175). Furthermore, blind- Recently, the structure of SLC26 proteins has been reviewed
ness arises in slc4a102/2 mice, which was suggested to occur (184). SLC26 proteins have three distinct regions: a variable
because of a failure to maintain appropriate cytosolic levels of cytoplasmic N-terminal region (51–106 amino acids), an inte-
Cl2 and HCO32 (176). gral membrane domain of 12 transmembrane segments, and a
cytoplasmic C-terminal STAS (sulfate transporter and anti-
NDCBE (SLC4A8). Na1-dependent chloride bicarbonate ex- Sigma factor antagonist) domain (185) related to those found
changer (NDCBE) is expressed mainly in central nervous in some bacterial proteins. SLC26 proteins are dimeric (186),
system. Unlike the other two electroneutral cotransporters, as also seen for SLC4 proteins.
NDCBE carries out electroneutral Na1-dependent Cl2/ The integral membrane domain of SLC26 proteins has
HCO32 exchange with the stoichiometry of 1:2:1 (Na1/ been the subject of few publications. Studies of SLC26 glycosy-
HCO32/Cl2, inward/outward/inward; ref. 22). lation site mutants led to detailed topology models for all
NDCBE in Disease. High NDCBE expression is found in pre- SLC26 proteins, each with 12 transmembrane segments and
synaptic terminals in close association with synaptic vesicles, cytosolic N- and C-termini (185). Homology modeling of
most glutamatergic axon terminals, and terminals of SLC26A6 on the basis of the E. coli ClC protein was able to
parvalbumin-positive c-aminobutyric acid (GABA)ergic cells predict functionally important residues, providing limited sup-
(177). Reduced acid extrusion in cultured hippocampal neurons port that SLC26 proteins share the ClC protein fold (45). None-
of slc4a82/2 mice along with increased seizure threshold in theless, there is an inconsistency as ClC proteins do not have
vivo suggests that NDCBE regulates pH to control presynaptic the 12-transmembrane segment structure that SLC26 proteins
glutamate release (178). Characterization of slc4a82/2 mice led have. A high-resolution structure for the membrane domain of
to the conclusion that NDCBE activity forms part of the an SLC26 protein will be required to resolve the issue.
thiazide-sensitive Na1 reabsorption pathway in the distal renal SLC26 STAS domains and adjacent sequences interact
tubule (179). Indeed, the emerging model is that in base- with other transporters (e.g., citrate transporter NaDC-1),
secreting (type B) intercalated cells of the distal renal tubule, cytoskeletal scaffolds, and with enzymes metabolizing trans-
apical SLC26A4 and NDCBE together accomplish net NaCl ported anion substrates, thereby forming a transport metabo-
reabsorption (179,180). lon (for review, see ref. 187). The SLC26A6 STAS domain binds
CAII (188) and interacts with the regulatory R-domain of CFTR
SLC4A9. Phylogenetically, SLC4A9 (also called AE4) clearly (189). The STAS domain is of great significance as so many
clusters with Na1-coupled bicarbonate transporters (Fig. 2), disease-causing mutations localize to this region (187).
for tubular Cl2, predominantly under conditions of metabolic tions predominantly as Cl2/HCO32 exchanger in acid-secreting
alkalosis, to regulate systemic pH (Fig. 4; ref. 198). Slc26a42/2 cells of outer medullary collecting duct (colocalized with AE1;
mice manifest acidic urine and downregulated epithelial cal- Fig. 4). Thus, deletion of slc26a7 in mice decreased basolateral
cium channel and Na1/Ca21 exchanger (causing hypercalciuria) HCO32 efflux, resulting in bicarbonate wasting which leads to
in the kidney (209). As discussed earlier, recent studies indicate dRTA (51). Similarly, in stomach, SLC26A7 functions in acid-
that NDCBE and SLC26A4 accomplish net NaCl uptake in type secreting gastric parietal cells (colocalized with AE2; Fig. 6),
B cells, with potential significance for hypertension (179,180). and thus, slc26a72/2 mice displayed decreased gastric acid
Kidney-targeted slc26a4 ablation leads to elevated HCO32 lev- secretion possibly due to impaired HCO32 efflux or enhanced
els in serum, consistent with failure of HCO32 secretion (210). Cl2 entry in parietal cells (51).
SLC26A6. SLC26A6 is expressed in pancreas, intestine, kidney, SLC26A9. SLC26A9 is expressed in brain, airway epithelial
heart, skeletal muscle, and placenta. SLC26A6 transports OH2, cells (223), gastric parietal cells (53), and collecting duct of
SO422, formate, oxalate, and NO32 anions; however, there are kidney (224). SLC26A9 functions in three modes: 1) electro-
species and splice variant-specific differences in coupling stoichi- genic Cl2/HCO32 exchange, 2) chloride channel, and 3)
ometry (46,47,211,212). Mouse SLC26A6 expressed in Xenopus Na1:Cl2 or HCO32 cotransport (53,225–227).
laevis oocytes carries out electrogenic Cl2/HCO32 exchange with
SLC26A9 in Disease. slc26a92/2 mice have a significant
isoform specific stoichiometry (1:2; refs. 33 and 191). Human
reduction of renal chloride excretion under high salt diet or
SLC26A6 expressed in X. laevis oocytes, however, exhibited elec-
when subjected to water deprivation (224). This work sug-
troneutral Cl2/HCO32 and Cl2/OH2 exchange with comparable
gested an important role played by SLC26A9 in renal chloride/
rates. In addition, human SLC26A6 had much slower chloride
fluid excretion and arterial pressure regulation, linking
and sulfate transport when compared with the mouse ortholog
impaired SLC26A9 directly to hypertension (224). Structural
(212). Cl2/HCO32 exchange activity of human SLC26A6 was
abnormalities in gastric parietal cell acid secretory apparatus
stimulated by cAMP and CFTR, but inhibited by the cystic fibro-
in slc26a92/2 mice implicate SLC26A9 in normal parietal cell
sis allele, F508del CFTR (212). Hence, the varying anion coupling
function (226). Finally, in human bronchial epithelial cells,
stoichiometry might depend on species and expression system.
SLC26A9 interacts with CFTR, where it acts as a Cl2 channel
SLC26A6 in Disease. Homozygous slc26a62/2 mice were under basal and cAMP/protein kinase A-stimulated conditions.
normal in terms of blood pressure and kidney function. Abol- More specifically, the role of SLC26A9 in human bronchial
ished oxalate-stimulated NaCl absorption, however, decreased cells requires functional CFTR (227).
apical Cl2/base exchange activity in the knockouts (213). Insol-
SLC26A11. SLC26A11 (also called KBAT [kidney brain anion
uble calcium oxalate is a key component of kidney stones. The
transporter]) was initially described as a SO422 transporter
presence of calcium oxalate stones in kidneys of slc26a62/2
(228). Guinea pig SLC26A11 expressed in X. laevis oocytes did
mice (214) suggests that variants of human SLC26A6 might
not transport HCO32, but did transport chloride, oxalate, and
contribute to stone formation, although this is yet to be estab-
sulfate (48). Cl2/HCO32 exchange activity has been reported
lished. Fructose ingestion induces hypertension, as a result of
only for mouse SLC26A11 (229). Human SLC26A11 facilitates
increased NaCl absorption. Interestingly, the phenomenon is
sulfate transport (228), although its ability to transport HCO32
absent in slc26a62/2 mice, leading to a hypothesis of fructose
has not apparently been assessed. Taken together, it is uncon-
stimulation of SLC26A6 (by means unknown), which increases
vincing that SLC26A11 can be regarded as a bicarbonate
intestinal NaCl absorption, leading to hypertension (215). Ele-
transporter. Recently, it was suggested that SLC26A11 is a Cl2
gant experiments on slc26a62/2 mice demonstrated the role of
channel, regulating acid translocation by H1-ATPase across
SLC26A6 acting in concert with NHE3 to achieve electroneutral
the plasma membrane and in intracellular compartments in
salt absorption in the small intestine (Fig. 8; ref. 216). Further-
Purkinje cells (230).
more, a role of SLC26A6 in HCO32 efflux at the apical mem-
brane of pancreatic ducts has been identified (Fig. 3; ref. 217). Bicarbonate Transport Metabolon
CAs are zinc metalloenzymes (EC 4.2.1.1) catalyzing reversible
SLC26A7. SLC26A7 localizes to the basolateral membrane of
hydration of CO2 to HCO32 and H1 (1). The 10 active CAs differ
gastric parietal cells (218), type A intercalated cells of the
in catalytic kinetics and cell location. CAII, the most widely dis-
outer medullary collecting duct (219), proximal tubule, and
tributed cytosolic isoform, has an enormous catalytic rate of
thick ascending limb of the loop of Henle (220). SLC26A7 facili-
about 106 s21. The extracellular membrane-associated iso-
tates electrogenic Cl2/HCO32 exchange (221) and has Cl2
forms are CAIV, CAIX, CAXII, and CAXIV. As CAs both produce
channel function (222). Oxalate and sulfate are also trans-
and consume the substrate of bicarbonate transporters,
ported, albeit more slowly than Cl2 (50).
HCO32, CA activity affects the rate of bicarbonate transport
SLC26A7 in Disease. No human diseases have yet been (231).
definitively associated with SLC26A7; however, the critical Considerable evidence led to the idea of a “bicarbonate
roles of the protein identified through mouse studies strongly transport metabolon” (71). A metabolon is a physical complex
suggest diseases associated with the protein. SLC26A7 func- of sequential enzymes in a metabolic pathway, where physical
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