SLC4 base (HCO3 , CO3 2 ) transporters ... - Renal Physiology
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<strong>SLC4</strong> <strong>base</strong> (HCO − 2−<br />
3 , <strong>CO3</strong><br />
) <strong>transporters</strong>: classification,<br />
function, structure, genetic diseases, and knockout models<br />
Alexander Pushkin and Ira Kurtz<br />
Am J Physiol <strong>Renal</strong> Physiol 290:F580-F599, 2006. ;<br />
doi: 10.1152/ajprenal.00252.2005<br />
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American Journal of <strong>Physiology</strong> - <strong>Renal</strong> <strong>Physiology</strong> publishes original manuscripts on a broad range of subjects<br />
relating to the kidney, urinary tract, and their respective cells and vasculature, as well as to the control of body fluid<br />
volume and composition. It is published 12 times a year (monthly) by the American Physiological Society, 9650<br />
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Invited Review<br />
� 2�<br />
<strong>SLC4</strong> <strong>base</strong> (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) <strong>transporters</strong>: classification, function, structure,<br />
genetic diseases, and knockout models<br />
Alexander Pushkin and Ira Kurtz<br />
Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, California<br />
� 2<br />
Pushkin, Alexander, and Ira Kurtz. <strong>SLC4</strong> <strong>base</strong> (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong><br />
�<br />
) <strong>transporters</strong>:<br />
classification, function, structure, genetic diseases, and knockout models. Am J<br />
Physiol <strong>Renal</strong> Physiol 290: F580–F599, 2006; doi:10.1152/ajprenal.00252.2005.—<br />
In prokaryotic and eukaryotic organisms, biochemical and physiological processes<br />
are sensitive to changes in H� activity. For these processes to function optimally,<br />
a variety of proteins have evolved that transport H� /<strong>base</strong> equivalents across cell<br />
and organelle membranes, thereby maintaining the pH of various intracellular and<br />
extracellular compartments within specific limits. The <strong>SLC4</strong> family of <strong>base</strong><br />
� 2�<br />
(<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>)<br />
transport proteins plays an essential role in mediating Na�- and/or<br />
Cl�-dependent <strong>base</strong> transport in various tissues and cell types in mammals. In<br />
addition to pH regulation, specific members of this family also contribute to<br />
vectorial transepithelial <strong>base</strong> transport in several organ systems including the<br />
kidney, pancreas, and eye. The importance of these <strong>transporters</strong> in mammalian cell<br />
biology is highlighted by the phenotypic abnormalities resulting from spontaneous<br />
<strong>SLC4</strong> mutations in humans and targeted deletions in murine knockout models. This<br />
review focuses on recent advances in our understanding of the molecular organization<br />
and functional properties of <strong>SLC4</strong> <strong>transporters</strong> and their role in disease.<br />
bicarbonate; transport<br />
� 2<br />
MEMBRANE PROTEINS THAT MEDIATE <strong>base</strong> (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong><br />
�<br />
) transport<br />
play an important role in eukaryotes in maintaining both<br />
intracellular pH (pHi) and extracellular pH (pHo) within nar-<br />
�<br />
row limits. This is not surprising given that the <strong>H<strong>CO3</strong></strong> /<br />
2� CO 3<br />
/CO2 buffer system is arguably the most important buffer<br />
in eukaryotic organisms. In mammals, two unrelated multigene<br />
families, <strong>SLC4</strong> and SLC26 <strong>transporters</strong>, have evolved, whose<br />
members transport <strong>base</strong> in both a cell type- and cell membranespecific<br />
fashion. This review focuses specifically on the <strong>SLC4</strong><br />
transporter family. The reader is referred to recent reviews on<br />
SLC26 <strong>transporters</strong> for an update on the role these <strong>transporters</strong><br />
play in health and disease states (46, 131). Following an initial<br />
overview of the classification of the <strong>SLC4</strong> family of transport<br />
proteins, we highlight recent advances in our understanding of<br />
the structure and function of these <strong>transporters</strong> and the role of<br />
protein interactions in the regulation of their functional properties.<br />
Abnormalities in either the function and/or membrane<br />
targeting of certain members of the <strong>SLC4</strong> family are the cause<br />
of various genetic diseases in humans. Mouse knockout models<br />
have also provided a useful adjunct with which to study the<br />
role of <strong>SLC4</strong> family members in specific organ systems.<br />
Advances in our understanding of the role of <strong>SLC4</strong> <strong>transporters</strong><br />
in health and disease are also the focus of this review.<br />
CLASSIFICATION OF <strong>SLC4</strong> TRANSPORTERS<br />
Based on the nature of the specific transport process involved,<br />
e.g., exchange, cotransport, and the specific ions that<br />
are transported, <strong>SLC4</strong> family members can be conveniently<br />
Address for reprint requests and other correspondence: I. Kurtz, Div. of<br />
Nephrology, David Geffen School of Medicine at UCLA, 10833 Le Conte<br />
Ave., Rm. 7–155 Factor Bldg., Los Angeles, CA 90095 (e-mail:<br />
ikurtz@mednet.ucla.edu).<br />
F580<br />
separated into three functional groups with potential transport<br />
� 2<br />
modes for <strong>H<strong>CO3</strong></strong> and/or <strong>CO3</strong><br />
�<br />
(Fig. 1): 1) Na�-independent Cl� �<br />
/<strong>H<strong>CO3</strong></strong> exchangers mediating electroneutral exchange of<br />
Cl� � 2<br />
for <strong>base</strong> (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong><br />
�<br />
); 2) Na� �<br />
-<strong>H<strong>CO3</strong></strong> co<strong>transporters</strong><br />
mediating cotransport of Na� � 2<br />
and <strong>base</strong> (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong><br />
�<br />
); and 3)<br />
Na�-driven Cl� �<br />
/<strong>H<strong>CO3</strong></strong> exchangers mediating the electroneutral<br />
exchange of Cl� for Na� � 2<br />
and <strong>base</strong> (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong><br />
�<br />
). <strong>SLC4</strong><br />
proteins have in common the property of transporting <strong>base</strong><br />
� 2<br />
(<strong>H<strong>CO3</strong></strong> , <strong>CO3</strong><br />
�<br />
) 1 but differ in their ability to mediate the<br />
concomitant transport of Na � and or Cl � . In addition, the<br />
cotransport of Na � by most <strong>SLC4</strong> <strong>transporters</strong> distinguishes<br />
this family from SLC26 proteins, which predominantly mediate<br />
Na � -independent anion transport. The sequences and classification<br />
of human <strong>SLC4</strong> <strong>transporters</strong> are shown in Fig. 2 and<br />
Table 1.<br />
Na�-Independent Cl� �<br />
/<strong>H<strong>CO3</strong></strong> Exchangers<br />
<strong>SLC4</strong>A1 (AE1). AE1 mediates Na�-independent anion exchange<br />
in red blood cells and the renal collecting duct. Two<br />
variants of AE1 have been well characterized (6, 25, 33, 107,<br />
123, 196). Red cell AE1 (eAE1) or band 3 protein (human<br />
�<br />
eAE1, 911 aa) plays an important role in transporting <strong>H<strong>CO3</strong></strong> to<br />
the lung that was derived from metabolically produced CO2.In<br />
the kidney, AE1 (kAE1) is transcribed from an alternate<br />
is �500:1, whereas at a typical pHi of 7.1,<br />
is twice this value, or �1,000:1. It is currently unclear as to<br />
(or both) is transported in various <strong>SLC4</strong> <strong>transporters</strong>.<br />
1 At pHo of 7.4, the <strong>H<strong>CO3</strong></strong> � /<strong>CO3</strong> 2 �<br />
Am J Physiol <strong>Renal</strong> Physiol 290: F580–F599, 2006;<br />
doi:10.1152/ajprenal.00252.2005.<br />
� 2<br />
the <strong>H<strong>CO3</strong></strong> /<strong>CO3</strong> �<br />
� 2<br />
whether <strong>H<strong>CO3</strong></strong> or <strong>CO3</strong> �<br />
The various potential transport modes are depicted in Fig. 1. At the present<br />
�<br />
time, the term “bicarbonate (<strong>H<strong>CO3</strong></strong> )” that is used in naming or describing the<br />
function (see Table 1) of <strong>SLC4</strong> <strong>transporters</strong> should not be viewed as a<br />
definitive description of the type of <strong>base</strong> transported, but rather as a term that<br />
� 2<br />
generically refers to <strong>H<strong>CO3</strong></strong> and/or <strong>CO3</strong> �<br />
until definitive studies are reported<br />
characterizing the specific species transported.<br />
0363-6127/06 $8.00 Copyright © 2006 the American Physiological Society http://www.ajprenal.org<br />
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Fig. 1. <strong>SLC4</strong> <strong>transporters</strong> can be divided functionally into 3 groups: Na�- independent Cl� � � �<br />
/<strong>H<strong>CO3</strong></strong> exchangers (A), Na -<strong>H<strong>CO3</strong></strong> co<strong>transporters</strong> (B), and<br />
Na�-driven Cl� � �<br />
/<strong>H<strong>CO3</strong></strong> exchangers (C). Potential transport modes for <strong>H<strong>CO3</strong></strong><br />
2�<br />
and <strong>CO3</strong> are depicted. In B,Na� �<br />
-<strong>H<strong>CO3</strong></strong> co<strong>transporters</strong> are further subdivided:<br />
(i) electroneutral Na� � � 2�<br />
-<strong>H<strong>CO3</strong></strong> co<strong>transporters</strong> with a <strong>H<strong>CO3</strong></strong> (<strong>CO3</strong> )-to-Na� transport stoichiometry of 1:1, and electrogenic Na� �<br />
-<strong>H<strong>CO3</strong></strong> co<strong>transporters</strong><br />
� 2�<br />
with a <strong>H<strong>CO3</strong></strong> (<strong>CO3</strong><br />
)-to-Na� transport stoichiometry of either 2:1 (ii) or3:1<br />
(iii) are shown. It has not been definitively established whether <strong>SLC4</strong> proteins<br />
� 2�<br />
mediate <strong>H<strong>CO3</strong></strong> and/or <strong>CO3</strong> transport. Depicted are the hypothetical modes of<br />
� 2�<br />
transport, wherein the coupling ratio of <strong>base</strong> (<strong>H<strong>CO3</strong></strong> and/or <strong>CO3</strong> ) transport to<br />
Na � and/or Cl � is equivalent. Note that these transport modes are not<br />
equivalent with regard to the total flux of carbon, hydrogen, and oxygen per<br />
transport cycle.<br />
promoter, and the resultant protein has an NH2-terminal truncation<br />
(first 65 amino acids in human AE1) (25). Kidneyspecific<br />
AE1 is expressed on the basolateral membrane of<br />
collecting duct �-intercalated cells (7, 205), where it plays an<br />
important role in bicarbonate reabsorption and urinary<br />
acidification.<br />
<strong>SLC4</strong>A2 (AE2). AE2 mediates Na � -independent anion exchange<br />
and is more widely expressed than AE1. Five NH2terminal<br />
splice variants of AE2 (a, b1, b2, c1, and c2) have<br />
been described in mammals and are expressed in a tissue- and<br />
cell-specific manner (5, 6, 8–10, 13, 40, 110, 129, 168, 217).<br />
Human AE2 is �300 aa larger than eAE1 and, like AE1, is<br />
glycosylated (6, 233). Deglycosylation of AE2 does not appre-<br />
� 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
Invited Review<br />
F581<br />
ciably affect its transport function (53). AE2 is widely expressed<br />
in nonexcitable tissues, where it has been proposed to<br />
be a housekeeping Cl � /HCO 3 � . It is also highly expressed on<br />
the basolateral membrane of choroid-plexus epithelial cells (9)<br />
and gastric parietal cells (191). In hepatocytes, AE2a, AE2b1,<br />
and AE2b2 have been localized to the apical membrane (13).<br />
In the kidney, AE2 is expressed in the basolateral membrane of<br />
the thick ascending limb (TAL) (6, 10). Ion transport mediated<br />
by AE2 expressed in Xenopus laevis oocytes (77, 188, 229) and<br />
mammalian cells (91, 115) is pH sensitive. Residues in the<br />
cytoplasmic NH2 terminus of mouse AE2, aa 336–347, 357–<br />
362, and 391–510, have been shown to regulate the pH dependence<br />
of the transporter (188–190, 229).<br />
<strong>SLC4</strong>A3 (AE3). AE3 mediates Na � -independent anion exchange<br />
like AE1 and AE2. Two NH2-terminal splice variants<br />
of AE3, cardiac (cAE3) and brain (bAE3), have been described<br />
(108, 118). The size of bAE3 (1,232 aa in humans) is comparable<br />
to AE2, whereas cAE3 is �200 aa shorter. Transcripts of<br />
both variants were found in different organs and tissues including<br />
the brain and heart (106, 108, 110, 118, 225). bAE3 protein<br />
has also been detected in basolateral membrane vesicles isolated<br />
from human ileal and colonic epithelial cells (11). AE3 is<br />
also expressed in the basal end foot processes of retinal Müller<br />
cells (106). AE3 expressed in X. laevis oocytes and HEK293<br />
cells mediates significantly less Cl � /HCO 3 � exchange than<br />
does AE1 or AE2 (53, 77, 115, 165, 225). Unlike AE2, when<br />
expressed in HEK cells, AE3 does not appear to be glycosylated<br />
(53). The decreased rate of AE3-mediated anion exchange<br />
in HEK cells has been attributed to a low level of<br />
plasma membrane targeting. cAE3 transport is stimulated at an<br />
alkaline pH similar to AE2 (188).<br />
Sodium Bicarbonate Co<strong>transporters</strong><br />
Sodium bicarbonate co<strong>transporters</strong> mediate cotransport of<br />
Na� � 2<br />
and <strong>base</strong> (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong><br />
�<br />
). 2 Depending on the flux of the<br />
net charge per transport cycle, these <strong>transporters</strong> are characterized<br />
�<br />
as electroneutral [i.e., transported negative charge (<strong>H<strong>CO3</strong></strong> and/or<br />
2<br />
<strong>CO3</strong> �<br />
)] equals transported positive charge (Na� ), or electro-<br />
� 2<br />
genic [i.e., transported negative charge (<strong>H<strong>CO3</strong></strong> and/or <strong>CO3</strong><br />
�<br />
)]<br />
exceeds transported positive charge (Na � ).<br />
<strong>SLC4</strong>A4 (NBC1, NBCe1). NBC1 is an electrogenic sodium<br />
bicarbonate cotransporter that was first cloned from Ambystoma<br />
tigrinum (166) and human (30) kidney. In humans, two<br />
major NBC1 variants, kNBC1 (NBCe1-A) (1,035 aa) and<br />
pNBC1 (NBCe1-B) (1,079 aa), that differ in their extreme NH2<br />
terminus are differentially expressed in a cell-specific manner<br />
(2) and are derived from alternate promoter usage in the<br />
<strong>SLC4</strong>A4 gene (4). A third NBC1 variant, rb2NBC (NBCe1c),<br />
has been cloned from rat brain and is identical to rat pNBC1<br />
except for 61 COOH-terminal residues and a COOH-terminal<br />
PDZ motif (18). Recently, a similar splice variant of the<br />
<strong>SLC4</strong>A4 gene has been detected in human and porcine vas<br />
2 As depicted in Fig. 1, in electrogenic sodium bicarbonate co<strong>transporters</strong>, a<br />
�<br />
2:1 stoichiometry could result for example from the transport of 2<strong>H<strong>CO3</strong></strong> �<br />
1Na� 2<br />
, 1<strong>CO3</strong> �<br />
� 1Na� � 2<br />
, or 2<strong>H<strong>CO3</strong></strong> � 1<strong>CO3</strong> �<br />
� 2Na� . A 3:1 cotransporter<br />
� � stoichiometry could result from the transport of either 3<strong>H<strong>CO3</strong></strong> � 1Na ,<br />
2<br />
3<strong>CO3</strong> �<br />
� 2Na� � 2<br />
, or 1<strong>H<strong>CO3</strong></strong> � 1<strong>CO3</strong> �<br />
� 1Na� . Although the total charge<br />
transported is identical, it is clear that the total carbon, hydrogen, and oxygen<br />
flux per transport cycle will differ and be dependent on the specific <strong>base</strong><br />
species transported, e.g., HCO 3 � vs. <strong>CO3</strong> 2 �<br />
.<br />
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Invited Review<br />
F582 � 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
Fig. 2. Alignment of human <strong>SLC4</strong> <strong>transporters</strong>: <strong>SLC4</strong>A1 (NP_000333), <strong>SLC4</strong>A2 (NP_003031), <strong>SLC4</strong>A3 (NP_005061), <strong>SLC4</strong>A4 (NP_003750), <strong>SLC4</strong>A5<br />
(NP_597812), <strong>SLC4</strong>A7 (NP_003606), <strong>SLC4</strong>A8 (NP_004849), <strong>SLC4</strong>A9 (NP_113655), and <strong>SLC4</strong>A10 (NP_071341). The alignment was performed using<br />
GeneWorks 2.5.1 software (Oxford Molecular Group, Campbell, CA). Putative transmembrane segments are shown in red (<strong>SLC4</strong>A1) and blue (<strong>SLC4</strong>A4) <strong>base</strong>d<br />
on topological models (198, 232). Amino acids shown to be important for <strong>SLC4</strong>A1- and <strong>SLC4</strong>A4-mediated transport (1, 35, 87, 97, 132, 133, 195, 231) are shown<br />
in bold font. Amino acids important for plasma membrane expression of <strong>SLC4</strong>A1 (54, 231, 232) and <strong>SLC4</strong>A4 (1, 75, 116) are marked with brown stars. Lysine<br />
residues shown to covalently bind DIDS and H2DIDS in <strong>SLC4</strong>A1 (93, 140) or homologous lysine residues in <strong>SLC4</strong>A4 predicted to covalently bind<br />
DIDS/H2DIDS are marked with ❖. Note that AE2 (<strong>SLC4</strong>A2), which has been shown to be inhibitable by DIDS (6), has methionine (M 1181 ) in a second putative<br />
DIDS binding site instead of lysine, whereas NBC3 (<strong>SLC4</strong>A7), which has been shown to be insensitive to DIDS (155), has lysines in both putative DIDS binding<br />
sites. Glycosylation sites for <strong>SLC4</strong>A1 (33) and <strong>SLC4</strong>A4 (38) are depicted with a branched tree symbol. <strong>SLC4</strong>A1, <strong>SLC4</strong>A2, and <strong>SLC4</strong>A4 amino acids that have<br />
been shown to play critical roles in binding of carbonic anhydrase II (CAII) (68, 154, 163, 206–208) are shown in magenta. CAII binding sites are depicted with<br />
a magenta line. The COOH-terminal PKA phosphorylation site in NBC1 is shown in green (arrowhead). Note that the <strong>SLC4</strong>A11 transporter NaBC1 is not<br />
included in the alignment despite its distant homology to the other members of the <strong>SLC4</strong> family, because recent studies have shown that it functions as a<br />
Na � -dependent borate transporter (142, 143, 145, 194).<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
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Table 1. Characteristics of <strong>SLC4</strong> <strong>transporters</strong><br />
deferens epithelial cells (148). NBC1 proteins have been<br />
shown to be glycosylated (38). kNBC1 is highly expressed on<br />
the basolateral membrane of the renal proximal tubule where it<br />
mediates sodium bicarbonate efflux (21, 127, 178, 223). In<br />
humans, the pNBC1 transcript is highly expressed in the<br />
pancreas and to a lesser extent in various other tissues (2).<br />
Unlike the kidney, wherein all studies agree on the localization<br />
of kNBC1, the expression pattern of pNBC1 in the<br />
pancreas is complex. NBC1 was localized with antibodies<br />
common to kNBC1 and pNBC1 to the basolateral membrane of<br />
large ducts in the human pancreas (125). In the rat pancreas,<br />
NBC1 was localized to the basolateral membrane of acinar<br />
cells, the apical and basolateral membranes of centroacinar<br />
cells, intra- and extralobular ducts, and main pancreatic duct<br />
cells (199). Localization of the pNBC1 variant to the basolateral<br />
membrane of pancreatic duct cells was further confirmed<br />
with a pNBC1-specific antibody (21). Satoh and coauthors<br />
(177), using kNBC1- and pNBC1-specific antibodies, reported<br />
that in human pancreatic ducts pNBC1 was expressed basolaterally<br />
and acinar cells were unstained, whereas in the rat<br />
pancreas acinar cells were stained basolaterally, and ductal<br />
cells expressed pNBC1 both apically and basolaterally. In<br />
addition, kNBC1 was localized apically in some ducts. Recently,<br />
in a similar study, Roussa and coauthors (169) found<br />
that pNBC1 was localized to the basolateral membrane of rat<br />
ductal and acinar cells and that pNBC1 and kNBC1 were<br />
localized together to the apical membrane of certain ductal<br />
cells. Moreover, these authors reported that in rat kidney<br />
pNBC1, in addition to kNBC1, was also localized to the<br />
basolateral membrane of S1 and S2 segments of the proximal<br />
tubule. It is clear that additional studies are needed to determine<br />
the reason for the varying results among different studies.<br />
The expression pattern of pNBC1 has also been characterized<br />
in corneal endothelium, duodenum, epididymis, vas deferens,<br />
and parotid and submandibular glands, where it is<br />
thought to mediate basolateral sodium bicarbonate influx (21,<br />
48, 89, 150, 170, 192, 193, 203). Species differences may<br />
determine differences shown for relative distribution of<br />
kNBC1 and pNBC1. For example, pNBC1 is expressed in<br />
various rat eye tissues including cornea, conjunctiva, lens,<br />
ciliary body, and retina, whereas the expression of kNBC1 is<br />
� 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
Invited Review<br />
Human Gene Protein Name Function Stoichiometry Electrogenicity<br />
<strong>SLC4</strong>A1 AE1, band 3 Cl � /HCO 3 � exchange 1:1 Electroneutral<br />
<strong>SLC4</strong>A2 AE2 Cl � /HCO 3 � exchange 1:1 Electroneutral<br />
<strong>SLC4</strong>A3 AE3 Cl � /HCO 3 � exchange 1:1 Electroneutral<br />
<strong>SLC4</strong>A4 NBC1, NBCe1 Na � -HCO 3 � cotransport 2:1;3:1 Electrogenic<br />
<strong>SLC4</strong>A5 NBC4*, NBCe2 Na � -HCO 3 � cotransport 2:1;3:1 Electrogenic<br />
<strong>SLC4</strong>A7 NBC3, NBCn1 Na � -HCO 3 � cotransport 1:1 Electroneutral<br />
<strong>SLC4</strong>A8 NDCBE Na � -driven Cl � /HCO 3 � exchange 2:1:1 Electroneutral<br />
<strong>SLC4</strong>A9 AE4† Cl � /HCO 3 � exchange 1:1 Electroneutral<br />
Na � -HCO 3 � cotransport 1:1 Electroneutral<br />
<strong>SLC4</strong>A10 NCBE† Na � -driven Cl � /HCO 3 � exchange 2:1:1 Electroneutral<br />
Na � -HCO 3 � cotransport 1:1 Electroneutral<br />
Names used in the literature for <strong>SLC4</strong> <strong>transporters</strong> are as follows: <strong>SLC4</strong>A1: eAE1, (band 3), kAE1; <strong>SLC4</strong>A2: AE2a,b1,b2,c1,c2; <strong>SLC4</strong>A3: bAE3, cAE3;<br />
<strong>SLC4</strong>A4: kNBC1 (NBC1a, NBCe1-A); pNBC1 (NBCe1-B, NBC1b, dNBC1, hhNBC, rb1NBC); rb2NBC (NBCel-C); <strong>SLC4</strong>A5: NBC4a, NBC4b, NBC4c<br />
(NBCe2-C), NBC4d, NBC4e, NBC4f; <strong>SLC4</strong>A7: NBC3 (NBCn1-A), NBCn1-B, NBCn1-C, NBCn1-D, NBCn1-E; <strong>SLC4</strong>A8: NDCBE, kNBC-3; <strong>SLC4</strong>A9: AE4a,<br />
AE4b; <strong>SLC4</strong>A10: rb1NCBE (NCBE-B), rb2NCBE, NCBE-A. *The NBC4c splice variant functions in mammalian cells as an electrogenic sodium bicarbonate<br />
cotransporter (176). The NBC4e splice variant has been reported to function in Xenopus laevis as an electroneutral sodium bicarbonate cotransporter (222). †The<br />
functional properties of these <strong>transporters</strong> is controversial (see text for details and references). The stoichiometry for <strong>SLC4</strong>A4 and <strong>SLC4</strong>A5 <strong>transporters</strong> reflects<br />
the HCO 3 � :Na � coupling ratio. For <strong>SLC4</strong>A8 and <strong>SLC4</strong>A10 <strong>transporters</strong>, the 2:1:1 stoichiometry reflects the <strong>H<strong>CO3</strong></strong> � :Na:Cl � coupling ratio.<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
F583<br />
restricted to the conjunctiva (21). In the human eye, kNBC1<br />
and pNBC1 appear to be more evenly distributed (202).<br />
<strong>SLC4</strong>A5 (NBC4, NBCe2). NBC4 was originally cloned from<br />
a human cardiac cDNA library (156). Six human NBC4<br />
COOH-terminal splice variants (NBC4a–f: 1,137, 1,074,<br />
1,121, 1,040, 1,051, and 760 aa, respectively) (156, 157, 222)<br />
have been cloned. The NBC4c splice variant has been shown to<br />
mediate electrogenic sodium bicarbonate cotransport when<br />
expressed in mammalian mPCT cells (176) and X. laevis<br />
oocytes (210). NBC4e mediated electroneutral sodium bicarbonate<br />
cotransport when expressed in X. laevis oocytes (222).<br />
NBC4e was identical to NBC4c except for deletion of the last<br />
70 aa and 2 aa substitutions (H612Y and A699T) that are not<br />
present in the human genome data<strong>base</strong>. If confirmed, NBC4e<br />
would be the first known example of a sodium bicarbonate<br />
cotransporter whose transport stoichiometry and electrogenic<br />
properties change as a result of a deletion/modification of<br />
specific residues. NBC4 transcripts are expressed in several<br />
organs and tissues (156). In rat hepatocytes, NBC4c protein has<br />
been localized to the basolateral (sinusoidal) plasma membrane,<br />
whereas intrahepatic cholangiocytes stain apically (3).<br />
In the kidney, NBC4c is also expressed on the apical membrane<br />
of uroepithelial cells lining the renal pelvis (3), where the<br />
cotransporter may play an important role in protecting the renal<br />
parenchyma from alterations in urine pH. Kristensen and<br />
colleagues (109) have recently reported that NBC4 potentially<br />
regulates the pH of sarcolemmal vesicles in skeletal muscle.<br />
<strong>SLC4</strong>A7 (NBC3, NBCn1). The electroneutral sodium bicarbonate<br />
cotransporter NBC3 was originally cloned from human<br />
skeletal muscle (155). Human NBC3 consists of 1,214 aa and<br />
is the first known stilbene-insensitive member of the <strong>SLC4</strong><br />
family. Subsequently, the rat ortholog of NBC3, the electroneutral<br />
sodium bicarbonate cotransporter NBCn1, was cloned<br />
from rat aorta (37). NBC3 (114) and NBCn1 (211) are apparently<br />
glycosylated to a greater extent than NBC1 proteins.<br />
Three rat NBCn1 splice variants named NBCn1-(B–D) were<br />
also cloned from rat aorta (37).<br />
<strong>SLC4</strong>A7 proteins are expressed in several tissues. NBC3<br />
protein is expressed in rat renal connecting tubule (114) and in<br />
rat and rabbit renal collecting ducts in the apical membrane of<br />
�-intercalated cells and the basolateral membrane of �-inter-<br />
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F584 � 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
calated cells (114, 161). NBCn1 was detected in intercalated<br />
cells in the medulla and, in addition, at the basolateral membrane<br />
of the rat medullary TAL and inner medullary collecting<br />
duct cells (151, 211). NBC3 was also highly expressed on the<br />
apical membrane of narrow cells in caput epididymis and light<br />
(clear) cells in corpus and cauda epididymis (158). The cotransporter<br />
apparently plays a role in pHi regulation in the outer<br />
medullary and inner medullary collecting ducts (113, 151,<br />
227). In addition, the cotransporter plays a role in basolateral<br />
bicarbonate transport in the medullary TAL (23, 82, 139),<br />
proximal duodenal villus cells (150), the basolateral domain of<br />
choroid plexus epithelial cells (152), and submandibular glands<br />
(58, 122).<br />
Cooper and colleagues (42) recently reported a deletion<br />
variant (NBCn1-E) in rat hippocampal neurons that lacks 123<br />
amino acids in the cytoplasmic NH2-terminal domain. The<br />
cotransporter may play an important role in regulating hippocampal<br />
neuronal activity.<br />
Na�-Driven Cl� �<br />
/<strong>H<strong>CO3</strong></strong> Exchangers<br />
<strong>SLC4</strong>A8 (NDCBE). The first Na�-driven Cl� �<br />
/<strong>H<strong>CO3</strong></strong> exchanger<br />
(NDCBE) was cloned by Romero and coauthors (167)<br />
from Drosophila and named Na�-driven anion exchanger 1<br />
(NDAE1). Its transport was blocked by stilbenedisulfonates<br />
and might not be strictly electroneutral. In addition, NDAE1<br />
was able to use OH� instead of bicarbonate. NDCBE (1,044<br />
aa) cloned from the human brain by Grichtchenko and colleagues<br />
(60) when expressed in X. laevis oocytes functions as<br />
aNa�-driven Cl� �<br />
/<strong>H<strong>CO3</strong></strong> exchanger, has a strict requirement<br />
� �<br />
for <strong>H<strong>CO3</strong></strong> , and is DIDS sensitive. Although CO2/<strong>H<strong>CO3</strong></strong> stimulates<br />
NDAE1-induced pHi changes, it is not clear whether<br />
� �<br />
NDAE1 mediates <strong>H<strong>CO3</strong></strong> transport per se because CO2/<strong>H<strong>CO3</strong></strong> could simply dissipate OH� in the adjacent unstirred layer.<br />
NDAE1 expressed in X. laevis oocytes also differs from human<br />
NDCBE in that it is associated with a Cl� current, as well as<br />
�<br />
an inward current caused by CO2/<strong>H<strong>CO3</strong></strong> . NDCBE transcripts<br />
are present in the brain, testis, kidney, and ovary (60).<br />
A splice variant of NDCBE (originally named kNBC-3) was<br />
cloned from mouse inner medullary collecting duct<br />
(mIMCD-3) cells and when expressed in X. laevis oocytes<br />
mediated electroneutral sodium bicarbonate cotransport (212).<br />
The chloride dependence was not studied, and therefore its<br />
functional properties remain unclear. More recently, Virkki<br />
and coauthors (209) reported the cloning of a Na�-driven Cl� �<br />
/<strong>H<strong>CO3</strong></strong> exchanger of �1,200 aa from squid giant fiber lobe<br />
(sqNDCBE). Unlike the transport process described in native<br />
squid axon (22), reversal of the Na� gradient alters the direction<br />
sqNDCBE transport, and Li� can support pHi recovery<br />
from an acid load nearly as well as Na� .<br />
<strong>SLC4</strong> Transporters Whose Function is<br />
Incompletely Characterized<br />
<strong>SLC4</strong>A9 (AE4). AE4 was originally cloned (AE4a, 955 aa,<br />
and AE4b, 939 aa) from rabbit �-intercalated cells (202) and<br />
was localized to the apical membrane of renal collecting duct<br />
�-intercalated cell. Rabbit AE4a expressed in X. laevis oocytes<br />
and COS cells mediated Na � -independent, DIDS-insensitive<br />
Cl � /HCO 3 � exchange. In a separate study, AE4 was localized<br />
to apical and lateral membranes of collecting duct �-intercalated<br />
cells in the rabbit (105). However, in rat and mouse<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
collecting ducts, AE4 was detected on the basolateral membrane<br />
of �-intercalated cells (105). AE4 is also expressed on<br />
the basolateral membrane of mouse submandibular gland duct<br />
(105). In contrast to the data of Tsuganezawa and colleagues<br />
(201), rat AE4 expressed in LLC-PK1 and HEK293 cells<br />
mediated DIDS-sensitive Cl � /HCO 3 � exchange (105). Parker<br />
and colleagues (144) characterized human AE4 (945 aa) expressed<br />
in X. laevis oocytes as an electroneutral sodium bicarbonate<br />
cotransporter without Cl � /HCO 3 � exchange activity.<br />
Whether these discrepancies arise from species-mediated differences<br />
in amino acid composition or expression systemspecific<br />
protein(s) potentially interacting with AE4 requires<br />
further study. Based on its amino acid sequence, AE4 is most<br />
homologous to electrogenic sodium bicarbonate co<strong>transporters</strong><br />
rather than AE1–3.<br />
<strong>SLC4</strong>A10 (NCBE). NCBE (1,088 aa) was originally cloned<br />
from a mouse insulinoma cell line and when expressed in X.<br />
laevis oocytes and HEK293 cells was reported to mediate<br />
Na � -driven Cl � /HCO 3 � exchange (213). Two splice variants<br />
have been subsequently cloned from rat brain and functionally<br />
expressed (57). rb1NCBE was similar to mouse NCBE except<br />
for a 30-aa insert in the NH2 terminus and was highly expressed<br />
in spinal cord and brain beginning in the embryo.<br />
rb2NCBE has an additional 18 aa in its COOH terminus, which<br />
ends with a PDZ motif. rb2NCBE is more highly expressed in<br />
astrocytes than rb1NCBE. Both transcripts mediated Na � -<br />
driven Cl � /HCO 3 � exchange when expressed in mouse fibroblast<br />
3T3 cells, but rb2NCBE was more active in pH regulation<br />
(57). A human ortholog of rb1NCBE, NCBE-B (1,118 aa), and<br />
its splice variant missing 30 aa in the NH2 terminus, NCBE-A,<br />
have been reported (39).<br />
NCBE transcripts have been detected in the peripheral nervous<br />
system and in nonneuronal tissues such as the choroid<br />
plexus, the dura, and some epithelia including the acid-secreting<br />
epithelium of the stomach and the duodenal epithelium (76)<br />
and kidney (153). rb1NCBE protein was highly expressed on<br />
the basolateral membrane of mouse and rat choroid plexus cells<br />
(152, 153). rb2NCBE protein has also been localized in preliminary<br />
studies to the basolateral membrane of mTAL intercalated<br />
cells in the inner medullary collecting duct and duodenal<br />
villus cells (153). In a preliminary study, Choi and coauthors<br />
(39) demonstrated that the human NCBE-B splice variant<br />
functions in X. laevis oocytes as an electroneutral Na � -HCO 3 �<br />
cotransporter. Whether experimental differences in the extent<br />
of Cl � depletion and/or expression systems account for these<br />
findings is currently unknown.<br />
<strong>SLC4</strong> Transporters That Do Not Transport Bicarbonate<br />
<strong>SLC4</strong>A11 (NaBC1). <strong>SLC4</strong>A11 (initially called BTR1) (145)<br />
was originally included in the <strong>SLC4</strong> family because of distant<br />
sequence homology to other family members. BTR1 has been<br />
renamed NaBC1 because it has been shown to function as a<br />
Na�-dependent borate transporter (143, 145). In the absence of<br />
borate, NaBC1 conducts Na� and OH� (H� ), whereas in the<br />
presence of borate, NaBC1 functions as a voltage-regulated,<br />
electrogenic Na� �<br />
-B(OH) 4 cotransporter with a stoichiometry<br />
of Na� �<br />
:B(OH) 4 �2. NaBC1 is the mammalian ortholog of the<br />
Arabidopsis thaliana borate transporter AtBor1 (194).<br />
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CHANNEL-LIKE PROPERTIES OF <strong>SLC4</strong> TRANSPORTERS<br />
Several electroneutral <strong>SLC4</strong> <strong>transporters</strong> also have channellike<br />
properties. AE1 in native X. laevis oocytes has an associated<br />
small conductive anion current (51). The Na � -driven<br />
Cl � /HCO 3 � exchanger cloned from Drosophila NDAE1 also<br />
mediates a small Cl � current and a HCO 3 � current (167). Choi<br />
and colleagues (37, 42) have shown that two rat ortholog splice<br />
variants of the human NBC3 (NBCn1-B and NBCn1-E) in both<br />
X. laevis oocytes and HEK293 cells have an associated ion<br />
conductance that, as they suggested, is likely mediated by the<br />
cotransporter per se rather than an associated protein, although<br />
the latter possibility has not been definitely ruled out. The<br />
associated current was stimulated by DIDS, is not bicarbonate<br />
dependent, and Na � appeared to be the predominant ion<br />
responsible for the current. The physiological importance of<br />
these data, as well as potential implications to the transport<br />
mechanism, is unclear.<br />
TRANSPORT STOICHIOMETRY<br />
The ion transport stoichiometry of <strong>SLC4</strong> <strong>transporters</strong> determines<br />
whether they are electroneutral or electrogenic (Table 1)<br />
(67, 112). The flux through electrogenic <strong>SLC4</strong> <strong>transporters</strong> is<br />
affected by both the membrane potential and the activity of the<br />
transported ion species. AE1–3 proteins exchange equivalent<br />
amounts of Cl� for <strong>base</strong> and are electroneutral (6, 33). Sodium<br />
bicarbonate co<strong>transporters</strong> mediate the transport of Na� and<br />
<strong>base</strong> with different stoichiometries per transport cycle. In<br />
NBC3 (NBCn1), the transport stoichiometry is 1:1, and, like<br />
AE1–3, this transport process is electroneutral (37, 155).<br />
NBC1 mediates the cotransport of one positive charge and<br />
either two or three negative charges per transport cycle (2, 30,<br />
62–64, 67, 68, 112, 166). NBC4 is also electrogenic and has<br />
been reported to have a 3:1 transport stoichiometry when<br />
expressed in mammalian cells (176) and a 2:1 stoichiometry in<br />
X. laevis oocytes (211). Human NDCBE exchanges Cl� for the<br />
equivalent of one Na� �<br />
and two <strong>H<strong>CO3</strong></strong> ions, and the process is<br />
electroneutral (60) (see Fig. 1 for other potential modes of<br />
transport). Although all studies agree that AE4 and NCBE are<br />
electroneutral <strong>transporters</strong>, their Cl� and Na� dependence are<br />
controversial (39, 57, 105, 144, 201, 213), and additional<br />
studies are required to determine their mode of transport.<br />
NBC1 and NBC4 <strong>transporters</strong> differ from other <strong>SLC4</strong> family<br />
members in that they are electrogenic. The net charge carried<br />
by NBC1 and NBC4 varies with their transport stoichiometry<br />
and is an important determinant of the direction of Na� and<br />
� 2<br />
<strong>H<strong>CO3</strong></strong> (or <strong>CO3</strong><br />
�<br />
) flux (Fig. 3) (67, 112). In addition, because<br />
the cell membrane potential induces changes in the flux of<br />
electrogenic sodium bicarbonate co<strong>transporters</strong>, the effective<br />
cell buffer capacity will also vary with the membrane potential<br />
(16). This provides an interesting mechanism for coupling<br />
unrelated transport processes such as the electroneutral monocarboxylate<br />
transporter via MCT1 (which transports H� and<br />
moncarboxylates) to changes in membrane potential in cells<br />
expressing kNBC1 (16).<br />
It had been originally thought that the transport stoichiometry<br />
of <strong>SLC4</strong> proteins is an inherent property of each transporter<br />
that remains fixed. However, Chernova and colleagues<br />
(35) showed that an E699Q mutation in mouse AE1 blocked<br />
electroneutral Cl� /Cl� anion exchange and created an electrogenic<br />
Cl� 2�<br />
/SO4 exchange process. These data indicated that a<br />
� 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
Fig. 3. HCO 3 � :Na � transport stoichiometry and ion gradients of the cotransported<br />
species determine the reversal potential (Erev) and therefore the direction<br />
of transport mediated by electrogenic <strong>SLC4</strong> <strong>transporters</strong> (67, 112).<br />
Depicted is the effect of changes in either intracellular-to-extracellular Na �<br />
concentration ([Na � ]i/[Na � ]o; A) or intracellular-to-extracellular HCO 3 � concentration<br />
([HCO 3 � ]i/[ <strong>H<strong>CO3</strong></strong> � ]o ; B) ratio on Erev of an electrogenic Na � -<br />
HCO 3 � cotransporter functioning with a <strong>H<strong>CO3</strong></strong> � :Na � cotransport stoichiometry<br />
of either 2:1 or 3:1. The plot was generated using the following equation:<br />
E rev � RT<br />
F�n � 1� ln �Na� i<br />
�HCO 3 � � i n<br />
� n<br />
�Na�o �<strong>H<strong>CO3</strong></strong> � o<br />
Invited Review<br />
F585<br />
where R, T, and F have their usual meaning, and n is the HCO 3 � :Na � transport<br />
stoichiometry. In A, [HCO 3 � ]i � 15 mM and [<strong>H<strong>CO3</strong></strong> � ]o � 25 mM. In B,<br />
[Na � ]i � 20 mM and [Na � ]o � 150 mM. When the membrane potential is<br />
more negative than the Erev, the cotransporter functions in the efflux mode,<br />
thereby contributing to transepithelial HCO 3 � absorption as in the renal<br />
proximal tubule. Although it is usually assumed that a cotransporter functioning<br />
in the 2:1 mode mediates HCO 3 � influx as in the pancreas, in the rabbit<br />
proximal tubule when the cotransporter functions in the 2:1 mode, at a<br />
basolateral membrane potential of about �50 mV, basolateral HCO 3 � efflux<br />
can be driven by a high [Na � ]i of �60 mM (175, 181).<br />
single amino acid substitution could shift an electroneutral<br />
transport process to an electrogenic one. In addition, following<br />
the cloning of the NH2-terminal variants of NBC1 (kNBC1 and<br />
pNBC1), it had been thought that kNBC1 functions in a 3:1<br />
(efflux) mode and pNBC1 functions in 2:1 (influx) mode.<br />
Gross and colleagues (63), however, showed that both <strong>transporters</strong><br />
can function in either a 2:1 or 3:1 mode depending on<br />
the cell type in which they were exogenously expressed. In<br />
addition, it was shown that the HCO 3 � :Na � transport stoichiometry<br />
of NBC1 (kNBC1 and pNBC1) can shift from 3:1 to<br />
2:1 following cAMP-induced PKA-dependent phosphorylation<br />
of kNBC1-Ser 982 /pNBC1-Ser 1026 (62, 64). Moreover, Asp 986<br />
and Asp 988 were also shown to be required for the cAMPinduced<br />
shift of kNBC1 stoichiometry (68). These residues are<br />
located in close proximity to the PKA phosphorylation site,<br />
K 979 KGS, and are part of a putative D 986 NDD motif that, in<br />
addition to a second motif, L 958 DDV, was shown to be involved<br />
in carbonic anhydrase II (CAII) binding (154).<br />
Based on these considerations, Gross and colleagues (67, 68)<br />
originally hypothesized that a potential mechanism for the<br />
cAMP-induced shift in stoichiometry of kNBC1 requires the<br />
binding/dissociation of CAII. Against this hypothesis was the<br />
subsequent finding by Pushkin and colleagues (154) that the<br />
PKA-dependent phosphorylation of Ser 982 does not decrease<br />
CAII binding in vitro. In addition to PKA-dependent phosphorylation,<br />
an increase in intracellular Ca 2� concentration shifts<br />
the stoichiometry of kNBC1 expressed in X. laevis oocytes<br />
from 2:1 to 3:1 (132). The mechanism for the Ca 2� -induced<br />
shift in stoichiometry is currently unknown. Additional studies<br />
have shown that PKA-dependent phosphorylation of pNBC1<br />
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F586 � 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
(KRKT 49 ) does not alter the transport stoichiometry but enhances<br />
flux through the cotransporter, thereby potentially playing<br />
an important role in secretin-induced stimulation of pancreatic<br />
bicarbonate secretion (62).<br />
TRANSPORTED BASE: HCO 3 � VS. <strong>CO3</strong> 2�<br />
It has not been definitively established whether <strong>SLC4</strong> pro-<br />
� 2<br />
teins mediate <strong>H<strong>CO3</strong></strong> and/or <strong>CO3</strong><br />
�<br />
transport. Depicted in Fig. 1<br />
are the hypothetical modes of transport wherein the net charge<br />
� 2<br />
per transport cycle by <strong>H<strong>CO3</strong></strong> and/or <strong>CO3</strong><br />
�<br />
with Na� and/or<br />
Cl� is equivalent. Müller-Berger and colleagues (135) suggested<br />
that the finding that carbonic anhydrase (CA) inhibition<br />
only altered the flux through the basolateral proximal tubule<br />
electrogenic sodium bicarbonate cotransporter (kNBC1) functioning<br />
in the 3:1 mode and not in the 2:1 mode could be used<br />
� 2<br />
to determine whether <strong>H<strong>CO3</strong></strong> and/or <strong>CO3</strong><br />
�<br />
was the transported<br />
species. These authors argued on theoretical grounds that when<br />
CA inhibitors decrease the flux through the cotransporter,<br />
2<br />
<strong>CO3</strong> �<br />
must be one of the transported species and that, in the 3:1<br />
2<br />
mode, 1<strong>CO3</strong> � � � �1<strong>H<strong>CO3</strong></strong> � 1Na are transported. Moreover,<br />
the finding that CA inhibition did not alter the flux in the 2:1<br />
2<br />
mode argued against <strong>CO3</strong> �<br />
� �<br />
flux in favor of 2<strong>H<strong>CO3</strong></strong> � 1Na<br />
being transported. More recently, it has been suggested in<br />
preliminary experiments that even in the 2:1 mode, kNBC1<br />
transports 1Na� 2<br />
and1<strong>CO3</strong> �<br />
(59).<br />
2<br />
Another potential approach to distinguish <strong>CO3</strong> �<br />
�<br />
from <strong>H<strong>CO3</strong></strong> transport is the use of equilibrium thermodynamics (112). In<br />
the presence of a stable PCO2 difference across a membrane<br />
with a functional kNBC1 for example (e.g., lipid bilayer), it<br />
was previously demonstrated that theoretically under these<br />
conditions, the respective reversal potential values for a<br />
� � 2<br />
3<strong>H<strong>CO3</strong></strong> � 1Na transport mode vs. a1<strong>CO3</strong><br />
�<br />
�<br />
� 1<strong>H<strong>CO3</strong></strong> �<br />
1Na� transport mode would differ. Another potential approach<br />
by which to distinguish these modes of transport would be to<br />
establish a stable pK difference across a membrane (112). This<br />
� 2<br />
is possible to accomplish because the <strong>H<strong>CO3</strong></strong> 3 <strong>CO3</strong><br />
�<br />
� H� reaction varies with ionic strength. There are, however, technical<br />
limitations that have thus far not been solved that have<br />
prevented these approaches from being used experimentally.<br />
Fig. 4. Phylogenetic tree of <strong>SLC4</strong> <strong>transporters</strong> created using<br />
the UPGMA analysis. Numbers on top of each line represent<br />
the relative difference between the specific sequences using<br />
GeneWorks software.<br />
STRUCTURE<br />
Primary Structure<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
Comparison of the primary structures of <strong>SLC4</strong> <strong>transporters</strong><br />
shows significant sequence homology especially in putative<br />
membrane domains (Fig. 2). On the basis of their amino acid<br />
sequence homology, <strong>SLC4</strong> <strong>transporters</strong> appear to be separated<br />
structurally into three groups (Fig. 4) that likely have an<br />
evolutionary basis: 1) <strong>SLC4</strong>A1, <strong>SLC4</strong>A2, and <strong>SLC4</strong>A3; 2)<br />
<strong>SLC4</strong>A4, <strong>SLC4</strong>A5, and <strong>SLC4</strong>A9; and 3) <strong>SLC4</strong>A7, <strong>SLC4</strong>A8,<br />
and <strong>SLC4</strong>A10. These groups are distinct from the known<br />
functional categorization of <strong>SLC4</strong> <strong>transporters</strong>, indicating that<br />
primary structure may not be a sufficient predictor of the<br />
functional properties of each transporter.<br />
Posttranslational Modifications<br />
Although all <strong>SLC4</strong> <strong>transporters</strong> have various sites for potential<br />
posttranslational modification, thus far AE1 and NBC1<br />
<strong>transporters</strong> have been studied in some detail. Human erythrocyte<br />
AE1 contains a single site of N-glycosylation (Asn642 )in<br />
the fourth exofacial loop (Figs. 2 and 5) that contains either a<br />
short complex oligosaccharide or an extended polylactosaminyl<br />
oligosaccharide (33). Approximately equal amounts of the<br />
different glycosylated forms of AE1 are found in human red<br />
blood cells. Recently, a novel glycosylation site at Asn555 in<br />
the third exofacial loop has been described in addition (36).<br />
kNBC1 has been shown to contain two normally glycosylated<br />
sites at Asn597 and Asn617 (38) located in the second exofacial<br />
loop (Fig. 6) (198). Human AE1 was also palmitoylated at<br />
Cys843 (36). Interestingly, this modification did not affect<br />
trafficking of the anion exchanger.<br />
kNBC1 and pNBC1 are phosphorylated in their common<br />
COOH-terminal PKA phosphorylation site, KKGS (62, 64,<br />
68). The PKA-mediated phosphorylation of Ser982 in kNBC1<br />
(Ser1026 in pNBC1) shifts the transport stoichiometry of both<br />
NBC1 variants from 3:1 to 2:1 (62, 64, 68). pNBC1 possesses<br />
an additional PKA site (KRKT49 ), involved in the regulation of<br />
pNBC1-mediated flux but not the cotransporter stoichiometry<br />
(62).<br />
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Topological Models<br />
Different algorithms predict 9–15 transmembrane segments<br />
in members of the <strong>SLC4</strong> family. Topological models have been<br />
experimentally evaluated in two <strong>SLC4</strong> <strong>transporters</strong>. The most<br />
extensively studied <strong>SLC4</strong> transporter, the anion exchanger<br />
AE1, was proposed to possess 12 (149), 13 (33, 54, 232), or 14<br />
transmembrane segments (70, 94), of which the first 8 are<br />
generally accepted to exist (Fig. 5). The models fit calculations<br />
of AE1 transmembrane area <strong>base</strong>d on a low-resolution twodimensional<br />
crystallography data of dimeric COOH-terminal<br />
membrane domain of AE1 (214). All AE1 models predict that<br />
the NH2 and COOH termini are localized intracellularly. Controversial<br />
experimental data regarding putative COOH-terminal<br />
transmembrane segments require use of high-resolution<br />
� 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
Invited Review<br />
Fig. 5. Human AE1 topology model <strong>base</strong>d on the work of Zhu and colleagues (232). Amino acids that are important for AE1-mediated transport are shown in<br />
red (acidic), blue (basic), and black (others). Green stars depict the residues involved in human disease.<br />
X-ray crystallography to precisely identify the number and<br />
location of AE1 transmembrane segments.<br />
Several studies indicated that the integrity of several cytoplasmic<br />
loops of AE1 is not essential for assembly into an<br />
anion transport-active structure. Coexpression of two pairs of<br />
complementary fragments of AE1 resulted in the generation of<br />
the stilbene disulfonate-sensitive uptake of Cl � into X. laevis<br />
oocytes, similar to expressed intact AE1 (69). For example, the<br />
pairs of fragments, which contained the first 8 and the last 6<br />
membrane spans, and the first 12 and the last 2 membrane<br />
spans, separated within cytoplasmic surface loops of the membrane<br />
domain, were able to generate stilbene disulfonatesensitive<br />
Cl � uptake. In contrast, the pairs separated in the<br />
second cytoplasmic loop were not active (216). Omission of<br />
Fig. 6. Human NBC1 (NBCe1) topological model (198). Amino acids that are important for NBC1-mediated transport are shown in red (acidic), blue (basic),<br />
and black (others). Green stars depict the residues involved in human disease. TM, transmembrane.<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
F587<br />
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Invited Review<br />
F588 � 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
any of single transmembrane segments except of spans 6 and 7<br />
caused complete loss of functional expression (70). The unusually<br />
stable association between the AE1 fragments divided<br />
in the second exofacial loop was suggested to indicate an<br />
existence of interactions between polar surfaces on amphiphilic<br />
portions of the third and fifth transmembrane spans. Most AE1<br />
fragments contained the necessary information to fold in the<br />
membrane (71).<br />
Tatishchev and colleagues (198) demonstrated that NBC1<br />
has 10 transmembrane segments, with the NH2 and COOH<br />
termini localized intracellularly (Fig. 6). Whether the difference<br />
in the number of transmembrane segments in AE1 and<br />
NBC1 is related to their specific functional properties remains<br />
to be determined.<br />
Tertiary Structure<br />
The tertiary structure of the members of <strong>SLC4</strong> family has<br />
only been partially determined. A low-resolution (20 Å) structure<br />
of the membrane domain of AE1 has been reported <strong>base</strong>d<br />
on electron microscopy and three-dimensional image reconstruction<br />
of negatively stained two-dimensional crystals (215).<br />
The dimeric membrane domain revealed a U-shaped structure<br />
with dimensions of 60 � 110 and a thickness of 80 Å. The<br />
structure is open on the top and at the sides, with the monomers<br />
in close contact at the <strong>base</strong>, and the basal domain was 40 Å<br />
thick. The upper part of the dimer consisted of two elongated<br />
protrusions, which formed the sides of a canyon, enclosing a<br />
wide space that narrowed down and converged into a depression<br />
at the center of the dimer on the top of the basal domain.<br />
This depression might represent the opening to a transport<br />
channel located at the dimer interface.<br />
The crystal structure of the NH2-terminal cytoplasmic domain<br />
of the human AE1 (aa 1–379) has been reported at a<br />
much higher (2.6 Å) resolution (230). A tight symmetrical<br />
dimer stabilized by interlocked dimerization arms contributed<br />
by both monomers was reported. The dimer fit within a<br />
rectangular prism of approximate dimensions 75 � 55 � 45 Å.<br />
Each subunit also included a larger peripheral protein binding<br />
domain with an ���-fold. The binding sites of ankyrin,<br />
deoxyhemoglobin, aldolase, and glyceraldehyde-3-phosphate<br />
dehydrogenase were localized in the structure.<br />
The COOH-terminal cytoplasmic domain of human NBC3<br />
(aa 1127–1214) expressed in Escherichia coli cells and analyzed<br />
by gel permeation chromatography and sedimentation<br />
velocity centrifugation had a Stokes radius of 26 and 30 Å,<br />
respectively (119). Shape modeling suggested that the COOH<br />
terminus had a rodlike shape with the dimensions of 16 � 190<br />
Å, which was supposed to promote binding of regulatory<br />
proteins (119).<br />
Oligomeric Structure<br />
It is not known whether <strong>SLC4</strong> <strong>transporters</strong> are functionally<br />
active in monomeric form or whether oligomerization is required<br />
for their activity. Numerous biochemical studies of<br />
mammalian AE1 have identified monomers, dimers, trimers,<br />
tetramers, and higher order oligomers and their mixtures (32,<br />
41, 50, 136). The relative abundance of these forms was<br />
dependent on the detergent used for isolation of AE1 and the<br />
temperature of isolation. In two-dimensional crystals of AE1<br />
(50), the protein subunits, each consisting of two AE1 mono-<br />
mers, were arranged with threefold symmetry, suggesting that<br />
a functionally active form of AE1 might be a dimer or/and even<br />
a hexamer. Based on these structural data and because a<br />
mixture of dimers and tetramers has been shown to represent<br />
the majority of AE1 in red blood cells (19, 32, 41, 50, 136, 141,<br />
215), it is widely accepted that a dimer is an active oligomeric<br />
form of AE1. On the basis of coimmunoprecipitation and<br />
functional expression in X. laevis oocytes of noncontiguous<br />
and overlapping pairs of membrane domains of human AE1,<br />
Groves and Tanner (70) hypothesized that transmembrane<br />
spans 1–5 and 9–12 are involved in, and spans 6–8, 13, and 14<br />
are not important for, dimerization of AE1.<br />
Dimers and to a lesser extent tetramers were also shown to<br />
be major components of bAE3 purified from rabbit renal<br />
microsomal membranes in the presence of Triton X-100 (160).<br />
Tetramers of bAE3 were further characterized by transmission<br />
electron microscopy of negatively stained ion-exchanger molecules<br />
(160). Image analysis of the tetramer micrographs<br />
revealed an anion exchanger molecule in which monomers<br />
were arranged with fourfold symmetry around a cavity in the<br />
center of the molecule, which could play a role of an iontransporting<br />
channel. Oligomers of human NBC1 and NBC3<br />
were also detected when these proteins were expressed in<br />
HEK293 cells (159).<br />
TRANSPORT MECHANISM<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
It is unusual that the same mutigene family contains transport<br />
proteins that function as exchangers (e.g., AE1, AE2,<br />
AE3, NDCBE) and co<strong>transporters</strong> (e.g., NBC1, NBC4) (Fig.<br />
1). AE1 exchanges equal amounts of Cl � for HCO 3 � by a<br />
ping-pong mechanism, wherein the transporter can be in either<br />
the inward-facing or the outward-facing state (52, 55, 72, 88).<br />
According to Jennings et al. (88), the AE1 catalytic cycle<br />
consists of one pair of exchanging anions per anion exchanger<br />
monomer. The transport rate is governed by a single AE1<br />
conformational change, which leads to the transfer of a single<br />
anion across the membrane (146). The dissociation/association<br />
of ions with AE1 occurs more quickly than the AE1 conformational<br />
changes leading to the translocation of the bound<br />
anion. Human AE1 has an intrinsic functional asymmetry;<br />
therefore, at near neutral pH and equal extra- and intracellular<br />
concentrations of Cl � , most of the anion exchanger molecules<br />
are in the inward-facing state (104).<br />
The stilbene inhibitor DIDS has been shown to bind preferentially<br />
to the outward-facing state of AE1 (88) and is inhibited<br />
by DIDS from outside (31, 96). In contrast to AE1, kNBC1<br />
was inhibited equally by intra- or extracellularly applied DIDS<br />
(74). In addition, H2DIDS has been shown to covalently bind<br />
Lys 539 and Lys 851 in human AE1 at physiological pH (140),<br />
whereas DIDS binds to Lys 851 only at pH �12 (93). According<br />
to current AE1 topological models, both lysine residues are<br />
located in transmembrane segments (54, 70, 111, 232). kNBC1<br />
(30, 166) and the pancreatic form of NBC1, pNBC1 (2), as<br />
well as all members the <strong>SLC4</strong> family with the exception of the<br />
electroneutral sodium bicarbonate cotransporter NBC3 (155)<br />
and rabbit AE4a (202) are stilbene inhibitable, supporting an<br />
idea of a possible shared mechanism(s) of ion transport. However,<br />
against this assumption is the finding that stilbene inhibition<br />
is not limited to the members of <strong>SLC4</strong> family, suggesting<br />
that the mechanism of this inhibition is nonspecific and<br />
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involves binding of stilbene to exposed lysine residues, leading<br />
to steric blocking of normal ion transport mechanism. For<br />
example, various members of the SLC26 anion exchanger<br />
family, which have shared no sequence homology with <strong>SLC4</strong><br />
<strong>transporters</strong>, are also stilbene sensitive (131).<br />
Kinetic studies of the electrogenic sodium bicarbonate cotransporter<br />
NBC1 suggest that contrary to AE1, binding of<br />
both sodium and bicarbonate to the cotransporter is required<br />
before a transport event (65, 90). Gross and Hopfer (66)<br />
developed a kinetic model in which bicarbonate and sodium<br />
bind to NBC1 in an ordered rather than a random manner.<br />
Using additional simplifying assumptions, they fitted the<br />
model to experimental current-voltage relationships obtained at<br />
different concentrations of Na � and HCO 3 � and predicted that<br />
binding of the ions to the cotransporter is voltage dependent,<br />
with an electrical coefficient of 0.2 at pH 7.5. The later<br />
suggested that HCO 3 � “senses” �20% of the membrane’s<br />
electric field on binding to the cotransporter or, in other words,<br />
that the binding site for HCO 3 � is located about one-fifth of the<br />
electrical distance into the membrane. Two basic amino acid<br />
residues, Lys 854 and His 907 , in transmembrane segments of<br />
kNBC1 (Fig. 6) (198) potentially involved in binding of<br />
bicarbonate (1) are located �20 and �10% of membrane width<br />
from the cytoplasmic side. Therefore, binding of bicarbonate to<br />
kNBC1 in the inward-facing conformation may fit the prediction<br />
of Gross and Hopfer (66).<br />
ION SELECTIVITY AND TRANSLOCATION<br />
In proteins that function as exchangers and co<strong>transporters</strong>,<br />
there are residues usually located outside transmembrane segments<br />
mediating ion selectivity, and residues usually located<br />
within transmembrane segments that are involved in ion binding<br />
and translocation (ion binding/translocation site) (44, 172,<br />
220). In the absence of the NH2-terminal domain, the COOHterminal<br />
domain of AE1 (61) and AE3 (108) was able to<br />
mediate Cl � /HCO 3 � exchange, suggesting that the NH2-terminal<br />
domain is not necessary for ion exchange. Several amino<br />
acid residues have been identified that might be involved in ion<br />
selectivity and binding/translocation of AE1. Specifically,<br />
treatment of human red cell AE1 with Woodward’s reagent K<br />
labeled only glutamate but not aspartate residues (86) and<br />
inhibited Cl � /Br � exchange, suggesting that glutamate residue(s)<br />
is involved in AE1-mediated ion transport. Pretreatment<br />
with 4,4�-dinitrostilbene-2,2�-disulfonate (DNDS) protected<br />
AE1 from binding and inactivation by Woodward’s reagent K,<br />
suggesting that the stilbene-binding site and the glutamate<br />
residue(s) are located close to each other. In addition to<br />
glutamate, lysine, arginine, and histidine residues have been<br />
shown to be essential for AE1 transport activity (73, 84, 126,<br />
140, 146, 219, 228).<br />
The importance of glutamate residue(s) in AE1-mediated<br />
transport was further confirmed when Glu 681 in transmembrane<br />
segment 8 of human red cell AE1 (Glu 699 in mouse AE1) was<br />
shown to be involved in the ion exchange function of human<br />
(86, 87) and mouse AE1 (35). Mutation of Glu 681 in human<br />
AE1 and a homologous residue in human AE2 (182) to neutral<br />
or basic amino acids blocked transport of monovalent anions<br />
(Cl � and bicarbonate) but did not change maximum sulfate/<br />
sulfate exchange. Interestingly, replacement of mouse AE1<br />
Glu 699 with aspartate blocked transport of both monovalent<br />
� 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
Invited Review<br />
F589<br />
and divalent anions (133). Replacement of mouse AE1 Glu 699<br />
with glutamine inhibited Cl � /HCO 3 � exchange, but the mutant<br />
anion exchanger mediated an electrogenic Cl � /SO 4 2� exchange<br />
when expressed in X. laevis oocytes (35). It was suggested (87)<br />
that Glu 681 is the binding site for H � , which is transported with<br />
SO 4 2� during AE1-mediated H � -SO4 2� cotransport, and can be<br />
alternately exposed to the intracellular and extracellular media.<br />
In addition, interaction of mouse AE1 Glu 699 with His 752 was<br />
shown to be important for pH sensitivity of Cl � transport at<br />
low pH (133). Recently, it was shown that an additional<br />
glutamate residue is involved in Cl � binding and is part of a<br />
second Cl � binding/transport site in the AE1 monomer (85).<br />
In human kNBC1 (Fig. 6), Asp 754 (glutamate in AE1–3)<br />
flanks transmembrane segment 6 and plays a key role in<br />
kNBC1-mediated sodium bicarbonate cotransport, suggesting<br />
that the decreased length of aspartic acid compared with<br />
glutamic acid may be related to sodium dependence of ion<br />
transport (1). In addition, Asp 555 , Glu 559 , Asp 647 , Asp 685 , and<br />
Asp 778 are important for kNBC1 function (1). Asp 685 , conserved<br />
in Na � -dependent <strong>SLC4</strong> <strong>transporters</strong> and AE4, is potentially<br />
involved in sodium binding/translocation (1). Asp 555 ,<br />
conserved in all <strong>SLC4</strong> <strong>transporters</strong>, is located in close proximity<br />
to Lys 559 , which has been suggested (1) to participate in<br />
bicarbonate binding and translocation.<br />
The involvement of mouse AE1 Lys 558 (Lys 539 in human<br />
AE1, Fig. 5) in AE1-mediated Cl � transport was hypothesized<br />
<strong>base</strong>d on site-directed mutagenesis data (134). This amino acid<br />
residue located in a transmembrane span is also a target for<br />
covalent binding of H2DIDS and DIDS (93, 140). Both<br />
H2DIDS (DIDS at pH �12) and pyridoxal phosphate bind<br />
another lysine residue, Lys 851 (100, 140) and inhibit AE1.<br />
Several lysine residues (Lys 559 , Lys 667 , Lys 668 , Lys 681 , Lys 770 ,<br />
Lys 771 , Lys 854 , and Lys 924 ) are functionally important for<br />
kNBC1 (1). Lys 854 is localized in transmembrane segment 8,<br />
which is conserved in Na � -dependent <strong>SLC4</strong> <strong>transporters</strong> and<br />
potentially involved in ion binding/translocation mediated by<br />
NBC1. Human kNBC1 Lys 559 and Lys 924 are potential targets<br />
for DIDS inhibition. These residues are located extracellularly<br />
(Fig. 6); however, it is known that stilbenes inhibit kNBC1<br />
from both extra- and intracellular locations (74). Based on<br />
these data, Abuladze and coauthors (1) hypothesized that this<br />
part of the extracellular loop 2 in NBC1 is able to migrate<br />
between extra- and intracellular compartments. In addition,<br />
these authors suggested that this region is involved in bicarbonate<br />
binding in NBC1. The second half of this loop contains<br />
naturally glycosylated Asn 597 and Asn 617 (38) and therefore is<br />
located extracellularly. Lys 667 , Lys 668 , Lys 681 , Lys 770 , Lys 771 ,<br />
and Lys 854 are probably involved in ion selectivity in NBC1.<br />
Four histidine residues located in transmembrane segments<br />
of mouse AE1, His 721 , His 752 , His 837 , and His 852 (His 703 ,<br />
His 734 , His 819 , and His 834 in human AE1, Fig. 5) were shown<br />
by site-directed mutagenesis to participate in AE1-mediated<br />
ion exchange (133, 134). Mouse AE1 His 852 was shown to play<br />
a key role in the control of pH dependence of Cl � transport<br />
(133). It was suggested that the formation of a hydrogen bond<br />
between His 852 and Glu 699 (Glu 681 in human AE1) is essential<br />
for the decrease in Cl � transport at low pH. In addition, His 834<br />
in human AE1 was shown to play an essential role in the<br />
protein conformational changes during the ion exchange and is<br />
located in close proximity to the anion translocation site (92).<br />
It was also hypothesized that all these histidine residues inter-<br />
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Invited Review<br />
F590 � 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
act with mouse AE1 Lys 558 (Lys 539 human AE1), the target of<br />
covalent binding of DIDS (93, 140). All these histidine residues<br />
except His 819 are conserved in <strong>SLC4</strong> <strong>transporters</strong> (Fig. 2).<br />
The only NBC1 homolog of these AE1 histidine residues<br />
located in transmembrane segments, kNBC1-His 907 (human<br />
AE1-His 834 ), was shown to be important for NBC1-mediated<br />
ion transport (1), suggesting that it can participate in bicarbonate<br />
binding/translocation. Human kNBC1-His 776 (His 734 in<br />
human AE1) located in the third intracellular loop is also<br />
important for kNBC1 function and apparently involved in<br />
bicarbonate selection (1), whereas the role of His 807 (His 734 in<br />
human AE1) has not yet been evaluated.<br />
Mutating Arg 509 and Arg 748 in mouse AE1 to lysine, threonine,<br />
and cysteine or lysine and glutamine, respectively,<br />
abolished Cl � /Cl � exchange activity in X. laevis oocytes (97).<br />
The Arg 734 mutant was supposed to be functionally inactive,<br />
whereas the Arg 509 mutant was possibly active but abnormally<br />
folded and therefore subsequently degraded. Because Arg 734 is<br />
conserved in AE1–3 and missing in Na � -dependent members<br />
of the <strong>SLC4</strong> family, including AE4, this residue may be<br />
responsible for Cl � binding/translocation in anion exchangers.<br />
In addition, the kNBC1 Arg 538 , Arg 680 , Arg 722 , Arg 881 , and<br />
Arg 943 conserved in the <strong>SLC4</strong> family are also important for<br />
cotransporter function (1, 75).<br />
Several uncharged amino acids were detected in kNBC1<br />
transmembrane segments (Ser 427 , Tyr 433 , Phe 656 , Ser 684 , and<br />
Ala 799 ) and in loops (Thr 485 , Ala 556 , Thr 671 , Thr 677 , and<br />
Thr 815 ) that are important for cotransporter function (1, 49, 75).<br />
Numerous uncharged amino acids in the membrane domain of<br />
AE1 have also been shown to be important for anion exchange.<br />
Tang and coauthors (195) mutated to cysteine the amino acids<br />
within and in close proximity to transmembrane segment 8.<br />
The cysteine mutants of this segment, Ala 666 , Ser 667 , Leu 669 ,<br />
Leu 673 , Leu 677 , and Leu 680 , and in addition the intracellular<br />
mutants of Ile 684 and Ile 688 were inhibitable by sulfhydryl<br />
reagents. It was suggested that these amino acids could be a<br />
part of a AE1 translocation pore (195). Analysis of single<br />
cysteine mutants in the COOH-terminal area of human AE1<br />
(Phe 806 -Cys 885 ) in the last two putative transmembrane segments<br />
identified certain key residues in the Val 849 -Leu 863<br />
region (231). The putative ion selectivity filter was located at<br />
Ser 852 -Leu 857 (231).<br />
INTERACTION WITH CA: A TRANSPORT METABOLON<br />
CAs are a multigene family of enzymes that catalyze the<br />
reversible synthesis of bicarbonate from CO2 and H2O (24,<br />
180, 183, 200). Inhibition of CA activity affects <strong>SLC4</strong> anion<br />
exchange and sodium bicarbonate cotransport function (28, 29,<br />
128, 174, 181, 186). Kifor and coauthors (102) on the basis of<br />
indirect evidence suggested first that red cell AE1 might<br />
interact with a cytosolic CA. Reithmeier and colleagues (163,<br />
206–208) demonstrated that the COOH terminus of AE1 binds<br />
CAII. Functional studies have demonstrated that CAII stimulates<br />
the transport function of AE1, AE2, and AE3 (45, 186).<br />
As a model for the CAII-mediated enhancement of HCO 3 �<br />
transport through AE1, it was hypothesized that a complex of<br />
AE1 and CAII functions in red blood cells as a transport<br />
metabolon. In this model, the efficiency of bicarbonate transport<br />
via AE1 is enhanced by the intermolecular transfer of<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
bicarbonate between CAII and AE1, thereby eliminating the<br />
slower cytoplasmic diffusion of HCO 3 � between the two proteins<br />
(163, 186, 187, 206–208). In addition to CAII, CAIV was<br />
shown to bind AE1–3 (185).<br />
It is known that inhibition of CA activity in the renal<br />
proximal tubule of the kidney significantly decreases the rate of<br />
transepithelial bicarbonate absorption and basolateral sodium<br />
bicarbonate efflux (28, 29, 128, 174, 181). Complete inhibition<br />
of CA by 0.1 mM acetazolamide (ACTZ) decreased the flux<br />
through exogenously expressed kNBC1 by �65% when the<br />
transporter functioned with a HCO 3 � :Na � stoichiometry of 3:1<br />
(68) as in the in vivo proximal tubule (28) without altering its<br />
stoichiometry. ACTZ does not inhibit kNBC1-mediated flux<br />
when the cotransporter functions in the 2:1 stoichiometry mode<br />
(68, 181).<br />
The COOH terminus of kNBC1 (kNBC1-ct) was shown to<br />
bind CAII in vitro with high (Kd � 0.2 �M) affinity (68). Two<br />
kNBC1 acidic motifs, L 958 DDV and D 986 NDD, are involved in<br />
this binding (154). The complex of kNBC1 with CAII functioned<br />
as a transport metabolon (154). In pancreatic ducts,<br />
where pNBC1 mediates the basolateral influx of bicarbonate,<br />
CAII is highly expressed (137, 138). pNBC1 has a COOH<br />
terminus identical to kNBC1, and transfection of HEK cells<br />
with nonfunctional CAII has a dominant-negative effect on<br />
pNBC1 function (12), suggesting that pNBC1 also forms a<br />
functional complex with CAII. pNBC1 also binds CAIV (12).<br />
The COOH terminus of electroneutral sodium bicarbonate<br />
cotransporter NBC3, like NBC1 and AE1-AE3, binds CAII<br />
with high affinity (Kd �100 nM) (119). The human NBC3-<br />
D 1135 -D 1136 residues were essential for the interaction between<br />
the two proteins. In �-intercalated cells in the outer medullary<br />
collecting duct, the interaction between apical NBC3 and CAII<br />
may play an important role in pHi regulation.<br />
In addition to CA, certain <strong>SLC4</strong> <strong>transporters</strong> interact with<br />
other cellular proteins. The cytoplasmic domain of AE1 contains<br />
sites for binding ankyrin, 4.1 and 4.2 proteins, glyceraldehyde-3-phosphate<br />
dehydrogenase, phosphofructokinase, deoxyhemoglobin,<br />
p72syk protein tyrosine kinase, and<br />
hemichromes (230) and functions as an anchoring site for these<br />
membrane-associated proteins. These interactions are important<br />
for regulation of cell flexibility and shape (121), glucose<br />
metabolism (120), ion transport (124), and cell life span (95).<br />
The AE1 NH2-terminal cytoplasmic domain is stabilized by<br />
interlocked dimerization arms contributed by both monomers<br />
(230).<br />
GENETIC DISEASES AND KNOCKOUT MODELS<br />
The crucial importance of <strong>SLC4</strong> <strong>transporters</strong> in regulating<br />
intracellular pH and transporting bicarbonate in various cell<br />
types is best exemplified by the phenotype resulting from an<br />
abnormality in the functional properties of several members of<br />
the family (Table 2).<br />
<strong>SLC4</strong>A1<br />
Patients with AE1 mutations tend to have either hereditary<br />
spherocytosis (HS) or distal renal tubular acidosis (dRTA) but<br />
not both abnormalities. The reason for the lack of overlap<br />
between these syndromes is not understood. The majority of<br />
patients with HS-associated AE1 mutations have an autosomal<br />
dominant inheritance with missense mutations that are distrib-<br />
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Table 2. Genetic diseases and mouse knockout models<br />
Gene Species Phenotype Inheritance Reference(s)<br />
<strong>SLC4</strong>A1 Human Anemia, spherocytosis, distal RTA, hypokalemia,<br />
hypercalciuria, nephrocalcinosis, nephrolithiasis<br />
uted throughout the transporter. The underlying abnormality<br />
thus far appears to be abnormal targeting to the plasma membrane<br />
due to misfolding of mutant <strong>transporters</strong>. In addition, a<br />
dominant-negative effect results in a decrease in wild-type (wt)<br />
AE1 membrane expression. Patients with autosomal dominant<br />
dRTA due to mutant AE1 have missense mutations in AE1-<br />
R589 (R589H, R589C, and R589S), S613F, A889X, G609R,<br />
and a truncation of 11 COOH-terminal residues, R901X (26,<br />
34, 83, 99, 171). The syndrome is characterized by abnormal<br />
urinary acidification, metabolic acidosis, nephrocalcinosis, hypercalciuria,<br />
and hypokalemia. Within a given family, the<br />
phenotypic expression can vary, likely because of background<br />
genes that are thus far unidentified (218).<br />
Studies of either red blood cells or heterologous expression<br />
systems demonstrated only modest changes in function that<br />
could not account for the urinary acidification abnormality in<br />
patients (26, 83). wt-AE1 in vivo and in polarized Madin-<br />
Darby canine kidney (MDCK) cells is targeted to the basolateral<br />
membrane. The predominant abnormality in the mutants<br />
characterized thus far in polarized MDCK cells (G609R and<br />
R901X) is the abnormal targeting of kAE1 to both the apical<br />
and basolateral membranes (47, 171). It is speculated that<br />
luminal bicarbonate secretion via mislocalized apical AE1<br />
decreases urinary acidification in these patients and that oligomerization<br />
of mutant AE1 with the wt-AE1 results in a<br />
dominant-negative effect by mistargeting wt-AE1 to the apical<br />
membrane. The magnitude and direction of apical AE1-mediated<br />
transport would be dependent on the respective cell/lumen<br />
HCO 3 � and Cl � gradients. Whether patients with abnormal<br />
luminal bicarbonate secretion can be distinguished by a higher<br />
than urinary PCO2 compared with patients with dRTA due to<br />
abnormal H � -ATPase function remains to be determined.<br />
Autosomal recessive dRTA is prevalent in Southeast Asia.<br />
Unlike patients with autosomal dominant dRTA, autosomal<br />
recessive dRTA presents earlier and tends to be of greater<br />
severity (14, 17, 98). These patients have been reported to have<br />
missense mutations in AE1 G701D, or various compound<br />
heterozygous combinations, including patients with G701D<br />
and the second allele having an in-frame AE1-400–408 deletion<br />
[called South Asian ovalocytosis (SAO)], (G701D/SAO),<br />
A858D/SAO, �V850/SAO, A858D/�V850, and G701D/<br />
S773P (27, 197, 204, 226). The G701D mutant functions and<br />
is targeted normally in red blood cells but not in �-intercalated<br />
cells, which lack the targeting of glycophorin A (GPA) that is<br />
expressed in the red cell membrane (197). AE1 SAO is unable<br />
� 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
AD, AR 14,17,26,27,34,47,83,98,<br />
99,103,164,171,179,<br />
197,204,218,221,226<br />
Bovine Anemia, spherocytosis, distal RTA AD 80<br />
Mouse knockout Anemia, spherocytosis, runting AR 147,184<br />
<strong>SLC4</strong>A2 Mouse knockout Growth retardation, achlorhydria, edentulous, abnormal<br />
spermatogenesis, embryonically lethal<br />
AR 56,130<br />
<strong>SLC4</strong>A3 Human (polymorphism) Generalized seizures 173<br />
<strong>SLC4</strong>A4 Human Short stature, basal ganglia calcification, mental retardation,<br />
cataracts, band keratopathy, proximal RTA, hypokalemia<br />
AR 49,75,78,79,81,116,177,202<br />
<strong>SLC4</strong>A5 Human (polymorphism) Hypertension 15<br />
<strong>SLC4</strong>A7 Mouse knockout Retinal degeneration, mild auditory impairment AR 20<br />
RTA, renal tubular acidosis; AD, autosomal dominant; AR, autosomal recessive.<br />
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F591<br />
to transport anions (179, 221). The A858D mutant functions<br />
abnormally, and its function is only partially rescued by GPA.<br />
In addition, the functioning of A858D is significantly decreased<br />
when coexpressed with �V850 or SAO (27). Similarly,<br />
the abnormal function of the �V850 mutant is not rescued<br />
completely by GPA (27). Recent detailed studies of the S773P<br />
mutant show that it is expressed at a low level, has a shorter<br />
half-life, is misfolded, and is targeted to the proteosome for<br />
degradation (103).<br />
Kittanakom and colleagues (103) have a proposed a model<br />
wherein AE1 mutants that cause autosomal dominant dRTA<br />
form heteroligomers with wt-AE1 that are retained in the<br />
endoplasmic reticulum, resulting in a dominant-negative effect.<br />
In contrast, AE1 mutants that cause autosomal recessive dRTA<br />
form homodimers which are targeted to the proteosome for<br />
degradation. Unlike mutants causing autosomal dominant<br />
dRTA, the S773P/wt-AE1 and G701D/wt-AE1 oligomers are<br />
targeted normally to the plasma membrane in HEK293 cells.<br />
Whether, as demonstrated with autosomal G609R and R901X<br />
mutations, homoligomers S773P and G701D homoligomers<br />
are targeted abnormally to the apical membrane in polarized<br />
cells remains to be determined. Interestingly, although patients<br />
with autosomal recessive dRTA typically have no red cell<br />
phenotype, patients with homozygous AE1-V488M have neonatal<br />
severe anemia and dRTA (164). Similarly, cattle homozygous<br />
for the AE1 R646X mutation have spherocytosis and<br />
dRTA (80). AE1 knockout mice have runting and severe<br />
anemia (147, 184).<br />
<strong>SLC4</strong>A2<br />
Although there are no known diseases in humans attributed<br />
to loss of AE2 function, targeted disruption of <strong>SLC4</strong>A2 in mice<br />
has recently been reported. Using a Cre/loxP strategy to disrupt<br />
expression of three of the four variants of AE2, Medina and<br />
coauthors (130) reported failure of spermiogenesis and infertility<br />
in male AE2�/� mice. Gawenis and colleagues (56)<br />
reported a more severe phenotype in AE2�/� mice related<br />
most likely to a different targeting strategy that resulted in the<br />
complete loss of AE2 expression. In this study, in some mice,<br />
loss of AE2 function was lethal to the embryo. In those<br />
AE2�/� mice that survived, most of them died around the time<br />
of weaning. The variability in survival suggests a role for<br />
background genes in modifying the severity of the phenotype.<br />
AE2�/� mice exhibited achlorhydria, moderate dilation of the<br />
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Invited Review<br />
F592 � 2�<br />
<strong>SLC4</strong> BASE (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong>) TRANSPORTERS<br />
gastric gland lumens, and a reduction in the number of parietal<br />
cells. Ultrastructural analysis revealed abnormal parietal cell<br />
structure, with severely impaired development of secretory<br />
canaliculi and few tubulovesicles but normal apical microvilli.<br />
In addition, the mice had severe growth retardation and were<br />
edentulous, ataxic, and almost deaf. These studies demonstrate<br />
the requirement for normal AE2 function in various organ<br />
systems and, specifically, the requirement of AE2 for normal<br />
gastric acid secretion and for normal development of secretory<br />
canalicular and tubulovesicular membranes in mouse parietal<br />
cells. In humans, it is probable that that total loss of AE2<br />
function is embryonically lethal.<br />
<strong>SLC4</strong>A3<br />
No genetic disease has been described for AE3. A significantly<br />
increased 2600 C/A polymorphism variant (A867D<br />
substitution) was detected in patients with idiopathic generalized<br />
epilepsies (173).<br />
<strong>SLC4</strong>A4<br />
Igarashi and colleagues (78) first reported two unrelated<br />
patients with homozygous mutations in the <strong>SLC4</strong>A4 gene. The<br />
patients were mentally retarded, with short stature and severe<br />
proximal renal tubular acidosis (pRTA), systemic academia,<br />
and hypokalemia. Ocular abnormalities included glaucoma,<br />
cataracts, and band keratopathy. The first patient had a missense<br />
R298S mutation (kNBC1 numbering) whereas the second<br />
patient had a R510H substitution. These mutations are<br />
predicted to affect both the kNBC1 and pNBC1 variants of the<br />
NBC1 (<strong>SLC4</strong>A4) gene. The serum amylase was elevated, and<br />
thyroid abnormalities were documented. A head computed<br />
tomographic scan revealed bilateral calcification of the basal<br />
ganglia. In a subsequent patient reported by the same group<br />
with a Q29X nonsense mutation affecting only kNBC1, the<br />
patient had severe pRTA and glaucoma without band keratopathy<br />
or cataracts (79). Both kNBC1 and pNBC1 are expressed in<br />
the eye in a cell type-specific fashion. In the rat eye, Bok and<br />
colleagues (21) detected pNBC1 in the ciliary body, conjunctival<br />
surface cells, cornea, lens epithelium, and retina, whereas<br />
kNBC1 expression was restricted to conjunctival basal cells.<br />
Usui and colleagues (202) reported a more widespread expression<br />
pattern of kNBC1 in various cell types in the human eye.<br />
The finding that the patient with the Q29X mutation only had<br />
glaucoma might suggest that band keratopathy and cataracts<br />
are due to pNBC1 mutations, whereas glaucoma is due to loss<br />
of function of kNBC1. However, other causes of congenital<br />
pRTA and systemic acidemia such as Lowe’s syndrome (43)<br />
also cause glaucoma and cataracts in addition to mental retardation<br />
and growth abnormalities, indicating that one should be<br />
cautious at this point in attributing a particular ocular phenotype<br />
to loss of function of either NBC1 variant in patients with<br />
<strong>SLC4</strong>A4 mutations. Dinour and colleagues (49) reported a<br />
patient with a homozygous S427L <strong>SLC4</strong>A4 missense mutation.<br />
The patient had severe pRTA, glaucoma, corneal opacities,<br />
cataracts, and abnormal dentition. A computed tomographic<br />
scan showed no calcifications, and the patient was of normal<br />
intelligence. Inatomi et al. (81) also recently reported a patient<br />
with a homozygous deletion of A2311 (kNBC1 numbering),<br />
resulting in anomalous transcription of 29 amino acids followed<br />
by a stop codon. The patient had severe pRTA, renal<br />
AJP-<strong>Renal</strong> Physiol • VOL 290 • MARCH 2006 • www.ajprenal.org<br />
insufficiency, elevated lipase and amylase levels, normal intelligence,<br />
glaucoma, corneal opacities, cataracts, tooth enamel<br />
defects, growth retardation, calcification of the basal ganglia<br />
and the left frontoparietal region, mild osteopenia, and normal<br />
thyroid function.<br />
Of the known NBC1 mutations causing pRTA in humans,<br />
several have been studied in heterologous expression system.<br />
The R298S and R510H missense mutations when assayed in<br />
ECV304 cells decreased the functional activity of kNBC1 by<br />
�55% (78). The same mutations in pNBC1 (R342S, R554H)<br />
also decreased the functional activity of pNBC1 by �50%<br />
(177). The S427L mutant that is targeted normally to the<br />
plasma membrane in X. laevis oocytes has significantly abnormal<br />
voltage and Na � -dependent transport (49). Interestingly,<br />
this mutant has no reversal potential accounting for the failure<br />
of kNBC1 to mediate sodium bicarbonate efflux in the kidney<br />
and eye. Horita and coauthors (75) recently identified three<br />
additional homozygous mutations (T485S, A799V, and<br />
R881C) in patients with severe pRTA and ocular abnormalities.<br />
Functional studies of these mutants in addition to the<br />
R298S and R510H mutants suggested that a 50% or greater<br />
reduction in kNBC1-mediated transport is required to cause<br />
severe pRTA (plasma HCO 3 � concentration � 13 mM).<br />
Li and coauthors (116) recently demonstrated that the kNBC1-<br />
R510H and S427L mutations not only have reduced intrinsic<br />
activity but are also mistargeted when expressed in polarized<br />
MDCK cells. The R510H mutant was predominantly retained in<br />
the cytoplasm, whereas the S427L mutant was mistargeted to the<br />
apical membrane. They also identified a kNBC1 COOH-terminal<br />
motif, QQPFLS (aa 1010–1015), is required for targeting of<br />
NBC1 to the basolateral membrane in MDCK cells (117). Within<br />
this motif, a kNBC1-F1013A mutant was abnormally targeted to<br />
the apical membrane. In a large-scale mutagenesis screen, Abuladze<br />
and coauthors (1) have shown that residues in several loops<br />
and transmembrane segments in kNBC1 are required for normal<br />
plasma membrane trageting. Studies of the kNBC1-A2311 deletion<br />
mutant failed to show any plasma membrane expression and<br />
functional activity in X. laevis oocytes (81).<br />
Recently, it has been suggested that the phenotype in patients<br />
with rod and cone degeneration (RP17 form of retinitis pigmentosa)<br />
due to missense mutations in CAIV results from an impaired<br />
wt-NBC1/CAIV transport metabolon in the endothelium of the<br />
choriocapillaris (224). The biologically active CAIV-R14W mutant<br />
did not stimulate NBC1 activity by failing to bind to NBC1,<br />
whereas the CAIV-R219S mutant did not stimulate NBC1 activity<br />
due to its enzymatic inactivity. Additional studies are needed to<br />
determine whether patients with NBC1 mutations have degenerated<br />
rods/cones and whether the ocular phenotype resulting from<br />
mutant CAIV can occur in the absence of functioning NBC1. In<br />
a separate study, Rebello and coauthors (162) have reported a<br />
different underlying mechanism for the RP17 form of retinitis<br />
pigmentosa. In patients with the CAIV-R14W mutation, their<br />
finding suggests that the mutant enzyme in endothelial cells in the<br />
choriocapillaris leads to ER stress due to an accumulation of<br />
unfolded protein, apoptosis, and ischemia of the retina.<br />
<strong>SLC4</strong>A5<br />
Polymorphisms in this gene are associated with hypertension<br />
(15). Further studies are needed to clarify the basis for this<br />
association.<br />
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<strong>SLC4</strong>A7<br />
Recently, the importance of NBC3 in sensory transduction<br />
has been demonstrated in an <strong>SLC4</strong>A7 knockout mouse (20).<br />
<strong>SLC4</strong>A7 knockout mice have a slow degeneration and ultimate<br />
loss of photoreceptors in the eye and a mild hearing defect due<br />
to the loss of inner and outer hair cells in the inner ear. These<br />
findings indicate that <strong>SLC4</strong>A7 knockout mice are a model for<br />
Usher syndrome, a group of diseases characterized by visual<br />
loss and auditory impairment in humans (101).<br />
CONCLUSION<br />
The <strong>SLC4</strong> family contains a functionally diverse group of<br />
transport proteins that play an essential role in the transport of<br />
� 2<br />
<strong>base</strong> (<strong>H<strong>CO3</strong></strong> ,<strong>CO3</strong><br />
�<br />
) in various tissues in mammals. Although<br />
there are have been numerous studies of the structure and<br />
function of the initial member of the <strong>SLC4</strong> family, AE1, more<br />
recently, additional members of the <strong>SLC4</strong> family have been<br />
investigated. Because of the efforts of several laboratories,<br />
various heterogeneous diseases can now be attributed to members<br />
of the <strong>SLC4</strong> family. Nevertheless, although much progress<br />
has been made, a thorough understanding of the structure and<br />
function of both wild-type and mutated <strong>transporters</strong> at a molecular<br />
level is lacking. The current topological models of AE1<br />
are still controversial because of the various methodologies<br />
used by different investigators to address this question. Because<br />
of these complexities, one cannot satisfactorily determine<br />
whether the larger number of transmembrane regions in<br />
AE1 compared with NBC1 represents differences in their ion<br />
binding sites/mechanism of transport. Nevertheless, recent<br />
studies on specific amino acid residues critical for NBC1mediated<br />
transport provide a structural basis for the molecular<br />
comparison of NBC1 and AE1. Results obtained thus far<br />
suggest that the molecular architecture and the transport mechanisms<br />
of NBC1 and AE1 have certain similar features, and at<br />
the same time, there are unique differences that might account<br />
for the separate transport modes (exchanger vs. cotransporter).<br />
In the future, successful crystallization of <strong>SLC4</strong> proteins will<br />
contribute to an understanding of their transport mechanism<br />
and help address these and other currently unresolved questions.<br />
GRANTS<br />
This work was supported by National Institutes of Health (NIH) Grants<br />
DK-63125, DK-58563, DK-07789, and ES-012935-A1, the Max Factor Family<br />
Foundation, the Richard and Hinda Rosenthal Foundation, the Fredrika<br />
Taubitz Fund, National Kidney Foundation of Southern California Grant<br />
J891002, and American Heart Association (Western State Affiliate) Grant<br />
0365022Y.<br />
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