Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

NBCe1 Electrogenic Na+-Coupled HCO3(CO32−) Transporter

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101572

Synonyms

Historical Background: SLC4 Gene Transporter Family

The NBCe1 transporter belongs to the SLC4 gene family whose 10 members are homologous membrane transport proteins that differ in their ability to transport Na+, Cl, HCO3(CO32−), H+, NH3, and water (Kurtz 2013; Parker and Boron 2013; Liu et al. 2015). AE1, AE2, and AE3 (SLC4A1, −2, −3, respectively) mediate the electroneutral exchange of Cl and HCO3. The SLC4A9 gene encodes AE4 has previously been reported to function as a Cl/HCO3 exchanger and electroneutral Na+-HCO3 cotransporter, but has recently been shown to mediate electroneutral monovalent cation (Na+/K+)-dependent Cl/HCO3 exchange (Pena-Munzenmayer et al. 2016). NDCBE (encoded by SLC4A8) like AE1, AE2, and AE3 is an anion exchanger yet differs in that it couples the electroneutral transport of Na+ and HCO3 (or CO32−) in exchange for Cl. NBCn1 (SLC4A7 gene) and NBCn2 (SLC4A10 gene) transport Na+-HCO3 electroneutrally. NBCn2 differs from NBCn1 in that a Cl/Cl exchange process is part of its transport cycle. NBCe1 (SLC4A4 gene) and NBCe2 (SLC4A5 gene) mediate electrogenic Na+-HCO3 and/or CO32− transport. SLC4A11 is the only member of the SLC4 family that does not transport HCO3 or CO32−. It is a multifunctional transporter that transports H+ in a Na+-coupled or independent mode and also mediates electrogenic H+-NH3 cotransport and water flux (Vilas et al. 2013; Zhang et al. 2015; Kao et al. 2016). Figure 1 shows a dendrogram of the SLC4 family demonstrating that in general, sequence similarity is predictive of a given transporter’s functional properties.
NBCe1 Electrogenic Na+-Coupled HCO3−(CO32−) Transporter, Fig. 1

SLC4 transporter dendrogram. Transporters with similar function tend to cluster based on the similarity of their amino acid sequence. The SLC4A11 gene is a multifunctional transporter lacking an accepted protein name

NBCe1 Variants

NBCe1 was functionally originally identified in the salamander proximal tubule (Boron and Boulpaep 1983) and subsequently cloned from salamander kidney (Romero et al. 1997). The SLC4A4 gene (Abuladze et al. 2000) encodes five NBCe1 variants (NBCe1-A-E) with NBCe1-D/E identified in mouse (Liu et al. 2011) (Fig. 2). These variants arise from two separate promoters and alternate slicing of exon 6 and exon 24 that results in differences in their N- and C-termini and the use of an alternate 9 aa cassette (Liu et al. 2011). All five variants have an identical transmembrane region but differ in their extreme N- and C-termini (Kurtz 2013; Parker and Boron 2013; Liu et al. 2015). Of the variants that have been functionally characterized and studied at the protein level, NBCe1-A, NBCe1-B, and NBCe1-C mediate electrogenic Na+-HCO3(and/or CO32−) transport but differ in their cellular localization, regulation, and intrinsic properties.
NBCe1 Electrogenic Na+-Coupled HCO3−(CO32−) Transporter, Fig. 2

The five known NBCe1 variants are depicted (not to scale). These variants share three separate regions that include: (1) N-terminal region (NTR); (2) transmembrane region (TMR); and (3) C-terminal tail (CTT). The five variants share an identical TMR and differ in their NTR and CTT. NBCe1-A and NBCe1-D only differ in their NTR where the -D variant lacks a stretch of 9 aa (RMFSNPDNG). NBCe1-B and NBCe1-E also only differ in their NTR where the -E variant also lacks the same 9 aa cassette. NBCe1-B and NBCe1-C differ in their CTT where the -C variant has a unique CTT with a type I PDZ motif. NBCe1-D and NBCe1-E transcripts were originally detected in mouse reproductive tissues (Liu et al. 2011) and have not yet been demonstrated at the protein level

Examples of organs/cells where NBCe1 plays an important transport role is shown in Fig. 3. In the kidney, NBCe1-A is localized to the basolateral membrane of the proximal tubule S1 and S2 segments with minimal expression in the S3 segment (Abuladze et al. 1998b; Marino et al. 1999a). The transporter plays a key role in proximal tubule transepithelial bicarbonate absorption (Romero et al. 1997; Abuladze et al. 1998a; Maunsbach et al. 2000; Skelton et al. 2010). In extrarenal tissues, NBCe1-A has been localized at the protein level in the eye (Bok et al. 2001; Usui et al. 2001) and salivary gland (Brandes et al. 2007). NBCe1-A mRNA transcripts have been detected in nasal submucosal glands (Lee et al. 2005). NBCe1-B which was originally cloned from pancreas is more widely expressed that NBCe1-A, and contributes to transepithelial bicarbonate transport and intracellular and extracellular pH regulation in various tissues (Ishiguro et al. 1996a, b; Abuladze et al. 1998a; Marino et al. 1999; Gross et al. 2001a). The NBCe1-B variant that is identical to NBCe1-A in its transmembrane and C-terminal regions has a unique extreme N-terminus wherein 85 aa replace the 41 aa in NBCe1-A. The tissues in which NBCe1-B has been localized either at the transcript or protein level include intestine, gall bladder, submucosal and salivary glands, nasal mucosa, lung, heart, brain, eye, skeletal muscle, and ameloblasts (Abuladze et al. 1998a; Choi et al. 1999; Bok et al. 2001; Usui et al. 2001; Kristensen et al. 2004; Lee et al. 2005; Kreindler et al. 2006; Moser et al. 2007; Perry et al. 2007; Majumdar et al. 2008; Paine et al. 2008; Yu et al. 2009; Abdulnour-Nakhoul et al. 2011; De Giusti et al. 2011; Garciarena et al. 2013; Jalali et al. 2014; Namkoong et al. 2015). It should be noted that several of these studies did not distinguish whether NBCe1-C/−E were potentially expressed. NBCe1-C, originally cloned from rat brain (McAlear et al. 2006; Majumdar et al. 2008), has a unique type I PDZ motif in its C-terminus. NBCe1-D and NBCe1-E transcripts found in mouse reproductive tissues are identical to NBCe1-A and NBCe1-B, respectively, except that in the cytosolic N-terminus they lack a nine amino-acid cassette (Fig. 2; Liu et al. 2011).
NBCe1 Electrogenic Na+-Coupled HCO3−(CO32−) Transporter, Fig. 3

Transport models of some of the cells/tissues that are involved in patients with pRTA mutations. (a) kidney proximal tubule, (b) pancreatic duct, (c) maturation stage ameloblast, (d) cornea

Charge Transport Stoichiometry Considerations and Anion Substrates: HCO3 Versus CO32− Transport

The direction of NBCe1 transport in cells and epithelia is determined by the electrochemical driving force (μ) across the transporter. The charge transport stoichiometry and the membrane potential are the two major determinants of the overall electrochemical driving force given that in all cells the chemical gradient for Na+ and base (HCO3, CO32−) is inward (extracellular to cytoplasm) (Kurtz et al. 2004). In the human kidney proximal tubule, it is widely assumed NBC1-A has a charge transport stoichiometry of 1:3 (1 Na+: 1 HCO3: 1 CO32−) and that the value of μ is positive leading to cellular base efflux. In the rat proximal tubule in vivo a charge transport stoichiometry of 1:3 was reported (Yoshitomi et al. 1985); however, in the isolated perfused rabbit proximal tubule, a value that varied from 1.2–1:2.7 was reported that depended on the composition of the experimental solutions used (Seki et al. 1993; Müller-Berger et al. 1997). In Necturus proximal tubules in vivo, the charge transport stoichiometry could be decreased from 1:3 to 1:2 as a result of acutely increasing the PCO2 (Planelles et al. 1993). Moreover, Gross et al. reported that the charge transport stoichiometry of NBCe1 could vary depending on the cell type in which the measurements were made (Gross et al. 2001b). In expression systems with excellent signal/noise and few technical artifacts, the charge transport stoichiometry of human NBCe1-A expressed in both human HEK293 cells and Xenopus oocytes is 1:2 (Lee et al. 2013; Zhu et al. 2013b). It is currently unknown whether the charge transport stoichiometry in vivo in humans can be modulated as has been reported in vitro with regards to changes in intracellular Ca2+ (Muller-Berger et al. 2001), an acute change in the PCO2 (Planelles et al. 1993), and altered phosphorylation status (Gross et al. 2001c).

The NBCe1 charge transport stoichiometry of 1:2 is compatible with either Na+-CO32− cotransport (one anion interaction site) or 1 Na+:2 HCO3 transport (two anion interaction sites). Given that NBCe1-B in secretory epithelia such as intestine, pancreas, and salivary glands and nonsecretory cells such as astrocytes normally mediates cellular Na+-coupled base influx, it is assumed that the transporter has a charge transport stoichiometry of 1:2. A value of 1:2 has been measured in cultured pancreatic cells (Gross et al. 2001a). Zhu et al. reported that human NBCe1-A expressed in HEK-293 cells functioning with a 1:2 charge transport stoichiometry transports Na+-CO32− based on experiments that utilized NO3 as a surrogate for CO3 transport (Zhu et al. 2013b). Surface pH measurements in Xenopus oocytes also suggest in preliminary experiments that rat NBCe1-A functions as a Na+-CO32− cotransporter (Lee et al. 2011).

In native human proximal tubule cells it will be very difficult to determine the charge transport stoichiometry of NBCe1-A. It remains possible that proximal tubule cell-specific factors modulate the stoichiometry in vivo altering the electrochemical driving force across the transporter. Given that human NBCe1-A has a charge transport stoichiometry of 1:2 in vitro in expression systems with excellent signal/noise, the question has arisen as to whether a 1:2 charge transport stoichiometry is sufficient to drive Na+-CO32− efflux in vivo. Although the necessary human data is unavailable, it has been shown using data from rat proximal tubules that μ of NBCe1-A would have a positive value resulting in Na+-CO32− efflux (that is very sensitive to changes in small changes in μ) (Zhu et al. 2013b). Given these findings, if NBCe1 mediates Na+-CO32− transport, a change in its name to NCCe1-A, i.e., sodium carbonate cotransporter electrogenic 1-A would more accurately reflect the transported species.

NBCe1 Mutations: Proximal Renal Tubular Acidosis

Proximal renal tubular acidosis (pRTA) is a syndrome caused by several diseases that impair proximal tubular bicarbonate absorption (Haque et al. 2012). The abnormality in proximal tubule bicarbonate transport can be isolated (Table 1) or associated with additional proximal tubule transport defects as part of Fanconi’s syndrome (Table 2). Net transepithelial proximal tubule bicarbonate absorption (apical to basolateral direction) is mediated by the coupling of apical NHE3 mediated H+ transport (to a lesser extent the apical H+-ATPase) and basolateral NBCe1-A HCO3(and/or CO32−) transport (Fig. 3 (Boron 2006; Hamm et al. 2013). Bicarbonate absorption is enhanced by membrane bound carbonic anhydrase enzymes that catalyze the CO2 hydration/dehydration reactions in the lumen and peritubular compartments, and cytoplasmic carbonic anhydrase that catalyzes the cytoplasmic conversion of CO2 into H+ and HCO3. In the absence of other proximal tubule transport defects (Fanconi’s syndrome), the only known cause of hereditary (autosomal recessive) pRTA is mutations in the SLC4A4 gene that affect basolateral NBCe1-A mediated transport (Igarashi et al. 1999). Because the majority of mutations also affect other NBCe1 transcripts, patients have an extrarenal phenotype in addition to proximal renal tubular acidosis that includes cataracts, band keratopathy, glaucoma, mental retardation, basal ganglia calcifications, migraine headaches, tooth enamel defects, and short stature. The constellation of findings is diagnostic of patients with NBCe1 mutations.
NBCe1 Electrogenic Na+-Coupled HCO3−(CO32−) Transporter, Table 1

Inherited Causes of Isolated pRTA and Associated Extrarenal Abnormalities

Gene

Protein

Inheritance

Renal phenotype

Extrarenal phenotype

CA2

CAII

Autosomal recessive

pRTA, dRTA, hypokalemia

Osteopetrosis involving axial skeleton, long bones with widening of metaphyses, and skull; growth defect; intracerebral calcification

aSLC4A4

NBCe1

Autosomal recessive

pRTA, hypokalemia

Glaucoma, cataracts, band keratopathy, increased serum amylase and lipase, enamel defects, intracerebral calcification, decreased IQ, growth defect

Unknown gene(s)

Unknown

Autosomal dominant

pRTA

Decreased radial bone density, thinner iliac cortices, subaortic stenosis, colomboma, growth defect

aHeadaches have been reported in patients with the R510H, L522P, and R881C missense mutations, 2311delA, and a homozygous C-terminal 65 bp-del. In heterozygous patients with the 65 bp-del and the L522P mutations, headaches also been reported and have been attributed to a dominant negative effect

NBCe1 Electrogenic Na+-Coupled HCO3−(CO32−) Transporter, Table 2

Disorders Causing pRTA with Fanconi’s Syndrome

Gene

Protein

Inheritance

Disease

ALDOB

Aldolase B

Autosomal recessive

Hereditary fructose intolerance

ARSA

Arylsulfatase A

Autosomal recessive

Metachromatic leukodystrophy

ATP7B

Cu++ transporting ATPase β peptide

Autosomal recessive

Wilson’s disease

CLCN5

2Cl-/H+ exchanger

X-linked

Dent’s disease 1

Complex IV

Cytochrome C oxidase

N/A

Cytochrome C oxidase deficiency

CTNS

Cystinosin

Autosomal recessive

Cystinosis

FAH

Fumarylacetoacetase

Autosomal recessive

Tyrosinemia type I

EEHADH

Peroxisomal bifunctional enzyme

Autosomal dominant

FRTS3

GALT

Galactose-1-phosphate Uridylyltransferase

Autosomal recessive

Galactosemia

MMAB

Methylmalonyl CoA mutase

Autosomal recessive

Methylmalonic acidemia

OCRL1

PIP2 5-phosphatase

X-linked

Dent’s disease 2

OCRL1

PIP2 5-phosphatase

X-linked

Lowe’s syndrome

PC

Pyruvate carboxylase

Autosomal recessive

Pyruvate carboxylase deficiency

SLC2A2

GLUT2

Autosomal recessive

Fanconi-Bickel syndrome

Since Igarashi et al. first described two patients with homozygous NBCe1 mutations (Igarashi et al. 1999), a total of nine missense mutations (NBCe1-A numbering: R298S, S427L, T485S, G486R, R510H, L522P, A799V, R881C, and Q913R), two nonsense mutations (Q29X, W516X), and two frameshift deletions (2311 delA and a C-terminal tail 65 bp-del) have been reported (Table 3) (Kurtz 2013). The NBCe1-A-Q29X mutation involving the NBCe1-A N-terminus (Igarashi et al. 2001; Azimov et al. 2008) could also potentially involve NBCe1-D (Liu et al. 2011). The patient reported with the NBCe1-A Q29X mutation did not have band keratopathy or cataracts as do typical patients implying that mutant NBCe1-A does not cause these ocular abnormalities. Mice with congenital loss NBCe1 (all variants) have a more severe phenotype than humans with decreased survival, severe volume depletion, and colonic obstruction (Gawenis et al. 2007; Lacruz et al. 2010; Yu et al. 2016). A neurologic and ocular phenotype has not been reported in mice since these abnormalities either might become manifest after a longer period of time or are unique to humans. Interestingly, mice with loss of NBCe1 have impaired proximal tubule ammonia metabolism including a decrease in phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and increased expression of glutamine synthetase (Handlogten et al. 2015). These data show that NBCe1 is essential for mediating proximal tubule bicarbonate absorption and also required for normal proximal tubule renal ammonia metabolism.
NBCe1 Electrogenic Na+-Coupled HCO3−(CO32−) Transporter, Table 3

aProximal RTA caused by NBCe1 mutations

Mutation

Location

Classification

Effect of Mutation

Q29X

N-terminal region

Nonsense

NBCe1-A protein truncation

R298S

N-terminal region

Missense

Mistargeting: apical/basolateral membranes

Abnormal interaction of the N- terminal region with the cytoplasmic region

S427L

TM1

Missense

Mistargeting: predominant apical membrane

Abnormal helix packing

Decreased GHCO3

Impaired IHCO3 reversal at −Vm

T485S

IL1

Missense

Altered ion interaction

Electroneutral transport

G486R

TM3

Missense

Altered ion interaction

R510H

TM4

Missense

ER retention

W516X

TM4

Nonsense

Truncation: all NBCe1 variants

L522P

TM4

Missense

ER retention

2311 delA

IL4

Frameshift

Truncation: all NBCe1 variants

A799V

H4

Missense

Intracellular retention

Decreased GHCO3

Bicarbonate-independent Gcation

R881C

EL5

Missense

ER retention

bQ913R

TM13

Missense

ER retention

65 bp-del

C-terminal tail

Frameshift

ER retention

aNumbered according to NBCe1-A amino acid sequence; GHCO3: bicarbonate conductance; Gcation: cation conductance; IHCO3: bicarbonate-dependent current; −Vm: negative plasma membrane voltages

bReported in a compound heterozygote (R510H/Q913R) patient

Patients with SLC4A4 mutations have a disease process that mechanistically depends on the type of mutation involving the transporter. For example, nonsense/frameshift mutations result in absence of the full-length NBCe1 protein whereas missense mutations can either perturb the intrinsic function of the transporter and/or impair plasma membrane processing/targeting because of misfolded protein that is targeted to the endoplasmic reticulum (Table 3). Migraine headaches are an interesting manifestation in that they appear to be mutation specific and have been reported in patients with R510H, L522P, R881C, 2311 delA, and 65 bp-del mutations (Suzuki et al. 2010). It is of interest that headaches were also been reported in heterozygous family members of a patient with a 65 base-pair C-terminal deletion and the L522P mutations. The underlying pathophysiology is conjectural and in homozygotes may be caused by misfolded ER retained NBCe1-B in brain astrocytes resulting in NMDA-mediated neuronal hyperactivity, whereas in heterozygotes mutant-wild type NBCe1-B hetero-oligomers might be retained in the ER (Suzuki et al. 2010; Yamazaki et al. 2013).

Proximal renal tubular acidosis due to NBCe1 mutations is inherited in an autosomal recessive Mendelian fashion unlike patients with distal renal tubular acidosis caused by another member of the SLC4 family, AE1, where both autosomal recessive and dominant inheritance patterns have been reported (Batlle and Haque 2012). It is currently unknown whether individuals who are heterozygous carriers for NBCe1 mutations have subtle defects in proximal tubule bicarbonate absorption and/or ocular and neurologic findings. Furthermore, there are no reports of patients with gain of function mutations although residues in NBCe1 have been identified whose substitution can stimulate NBCe1 transport (Abuladze et al. 2005). Yamazaki et al. studied several NBCe1 SNPs including E122G, S356Y, K558R, and N640I in vitro and reported that the function of K558R was decreased 41–47% (Yamazaki et al. 2011). It would be of interest to determine the potential impact of these SNPs on proximal tubule bicarbonate absorption and ocular and neurologic function in animal and human studies.

In addition to patients with NBCe1 mutations, a familial form of isolated pRTA has also been reported that appears to be inherited in an autosomal dominant Mendelian fashion. The extrarenal manifestations differ in that these patients have decreased bone density and short stature (Table 1) (Brenes et al. 1977; Lemann et al. 2000; Katzir et al. 2008). The cause of this syndrome is currently unknown as mutations in the coding region of proximal tubule H+/base transport proteins including NBCe1, NHE3, NHE8, CAII, CAIV, CAXIV, PAT1(CFEX), NHERF1, and NHERF2 have been ruled out (Katzir et al. 2008). Whether mutations in intronic and promoter regions encoding any of these proteins are present has not yet been determined.

NBCe1 Mutations: Extrarenal Manifestations

Although some progress has been made, we currently lack a complete understanding of the cause of many of the extrarenal manifestations in patients for the following reasons: (1) NBCe1 dysfunction at the cellular level versus the effect of chronic systemic acidemia needs to be more precisely defined; (2) Additional work also needs to be done to determine the relative contribution of specific NBCe1 variants in affected cell types; and (3) The tissue distribution of each variant is not precisely known because several of the studies utilized antibodies that were unable to distinguish among certain variants i.e., NBCe1-B/-C/-E for example.

Patients with NBCe1 mutations have growth retardation that is not unique to this disorder in that decreased growth occurs in other pediatric diseases where metabolic acidosis is present from birth (Batlle and Haque 2012; Haque et al. 2012). Of interest, normal fetal blood is acidic in comparison to maternal blood, and it is conceivable that prior to birth the blood of babies with NBCe1 mutations might differ from normal (Spackman et al. 1963). A similar process might be occurring in other diseases where metabolic acidosis is present at birth.

Given the known expression of NBCe1 variants in the cortex and hippocampus (Majumdar et al. 2008), abnormal brain development and low IQ are more likely due to the loss of NBCe1 function in specific cell types in the brain. The role of the systemic acidemia is unclear but in general is not associated per se with this phenotype (Majumdar et al. 2008). Patients with NBCe1 mutations have calcified basal ganglia (Igarashi et al. 1994) as do patients with CAII mutations (Bosley et al. 2011). NBCe1 transcripts are expressed in the striatum and although conjectural, the calcification might be due to an elevated pH in this region due abnormal HCO3(CO32−) transport leading to calcium phosphate precipitation.

NBCe1 is expressed in several parts of the eye (Bok et al. 2001; Usui et al. 2001) and loss of its transport functions results in multiple abnormalities including band keratopathy, glaucoma, and cataracts. The mechanism for these abnormalities is poorly understood. With regards to band keratopathy, normal eyelid opening during blinking creates a brief loss of CO2 acutely alkalizing the anterior corneal tear coat (Fig. 3). We have hypothesized that the elevated corneal pH would normally be decreased towards normal by an increase in endothelial cell NBCe1-B transport. In patients with NBCe1 mutations, defective NBCe1-B transport would prevent the corneal pH from being regulated towards normal resulting in calcium phosphate precipitation (band keratopathy) in the central cornea, the region of the cornea that is exposed during eyelid opening. The mechanism for lens cataracts in these patients is not known. Previous studies have shown that toad lens epithelial cells have electrogenic Na+-base transport (Wolosin et al. 1990) that is likely mediated by NBCe1-B (Bok et al. 2001). NBCe1-B is expressed in the rat lens epithelium (Bok et al. 2001), where it is possible that defective cellular HCO3(and/or CO32−) transport and the resultant abnormal lens pH alters lens transparency. NBCe1-B is expressed in the rat pigmented ciliary body (Bok et al. 2001), and Woloson et al. has demonstrated electrogenic Na+-base transport process in rabbit ciliary body (Wolosin et al. 1993). How the loss of NBCe1 activity leads to glaucoma is also currently unknown.

In teeth, the extracellular matrix is calcified during enamel formation and this process mediated by ameloblasts is highly pH dependent. Patients with NBCe1 mutations have abnormal tooth enamel (Dinour et al. 2004) that has been attributed to abnormal pH regulation of the extracellular matrix due to loss of local ameloblast NBCe1 transport (Fig. 3) (Lacruz et al. 2010; Lacruz et al. 2012). Ameloblasts express several of the NBCe1 variants including NBCe1-B and/or -D/E and NBCe1-C protein (Paine et al. 2008; Jalali et al. 2014). Similar abnormalities have not been found in other patients with congenital or chronic metabolic acidosis suggesting that systemic acidemia and/or a decrease in salivary pH is not responsible for the phenotype in patients with NBCe1 mutations. Interestingly, however, in a study where mandibular E11.5 explants from NBCe1−/− mice were maintained in host kidney capsules of normal mice for 70 days, tooth enamel and dentin had morphological and mineralization properties similar to cultured NBCe1+/+ mandibles. If these findings can be extrapolated to patients, the results suggest that the cause of the enamel phenotype is primarily to be due to abnormalities in systemic pH (Wen et al. 2014).

In the pancreas, NBCe1-B is localized to the ductal cell basolateral cell membrane where it plays a role in cellular HCO3(CO32−) influx and transepithelial HCO3(CO32−) secretion (Fig. 3) (Ishiguro et al. 1996a, b; Marino et al. 1999; Gross et al. 2001a; Satoh et al. 2003). Unlike in cystic fibrosis where transepithelial bicarbonate secretion is thought to be defective, the loss of NBCe1-B function does not lead to any clinically apparent ductal abnormalities perhaps because of the upregulation of additional basolateral membrane bicarbonate influx pathways (Park and Lee 2012). Patients with NBCe1 mutations have increased serum amylase and lipase suggesting that acinar cell function is perturbed despite the fact that in humans acinar cells have not been shown to express NBCe1; although NBCe1-B is expressed in rat acinar cells. In mice, loss of NBCe1 leads to a severe intestinal GI phenotype (Gawenis et al. 2007; Yu et al. 2016). NBCe1-B is expressed in the human intestine; however, the loss of the transporter in patients with NBCe1 mutations does not lead to an obvious phenotype suggesting the possibility that either compensatory transport mechanisms come into play, and/or NBCe1-B plays a less important transport role in the normal physiology of the human GI tract.

NBCe1 Mutations: Structure-Function Properties

Within the SLC4 transporter family, the structural properties of NBCe1-A and AE1 have been most thoroughly studied. The structural properties of NBCe1-A provide a topologic framework not only for other NBCe1 variants because they share an identical transmembrane region, but also potentially there are insights that can be applied to other Na+-coupled SLC4 bicarbonate transporters. Fluorescence image moment studies and spatial intensity distribution analysis (SpIDA) have demonstrated that NBCe1-A is a dimer in the native kidney in situ (Sergeev et al. 2012). The dimerization state of the N-terminal region can potentially be modulated by changes in intracellular pH and/or bicarbonate (Gill 2012). Each monomer consists of 1035 amino acids (∼140-kDa glycoprotein) and can independently transport ions (Kao et al. 2008). In addition, the dimeric state per se plays a role functionally (Chang et al. 2014). The topologic structure of NBCe1 is subdivided into three separate regions that include a long N-terminal cytoplasmic region, a large transmembrane region, and a shorter C-terminal cytoplasmic tail. Zhu et al. using cysteine scanning mutagenesis to analyze the topologic properties of NBCe1-A showed that the transporter has 14 transmembrane segments (TMs) (Fig. 4). All NBCe1 variants have a large glycosylated extracellular loop between TMs 5 and 6 (Choi et al. 2003) that is not accessible to enzymatic digestion and is compactly folded within the protein (Zhu et al. 2015). An additional small extracellular loop is present between TMs 7 and 8. Both the N-terminal region and C-terminal tails of NBCe1 protein variants are located in the cytoplasm. It has been hypothesized that certain topologic features in NBCe1 might resemble the vGLUT and LeuT prokaryotic Na+-coupled transporters (Yamashita et al. 2005; Watanabe et al. 2010; Zhu et al. 2010a, b).
NBCe1 Electrogenic Na+-Coupled HCO3−(CO32−) Transporter, Fig. 4

(a) Linear topology of NBCe1-A. Known pRTA mutations are depicted (NBCe1-A numbering)

N-Terminal Cytoplasmic Region

A preliminary crystal structure of the NBCe1-A N-terminal cytoplasmic region has been reported (Gill et al. 2015). Alignment with AE1 shows similar hydrophobic residues and predicted helical regions. Within the N-terminal cytoplasmic region two NBCe1 mutations have previously been identified: A Q29X nonsense mutation that was initially thought to be specific for NBCe1-A yet would be predicted to also truncate NBCe1-D; and a R298S mutation that is shared by all NBCe1 variants. The potential for mutation specific therapy was demonstrated for the first time in the context of the Q29X mutation (Azimov et al. 2008). This mutation results in a wt-CAG sequence encoding glutamine being replaced by a UAG stop codon causing premature truncation of the transporter (Igarashi et al. 2001). In HEK 293-H cells expressing the NBCe1-A-Q29X mutant, ribosomal read-through was induced by the aminoglycoside G418 resulting in the production of full-length functional NBCe1-A protein (Azimov et al. 2008). The findings in this study suggested the possibility of treating the ocular abnormalities in patients using topical aminoglycosides and avoiding their systemic toxicity. In the future, it may be possible to treat patients with stop codon mutations with less toxic more potent aminoglycosides that have a flexible N-1-AHB group ((S)-2-hydroxy-4-aminobutyl group at the N-1 position) (Nudelman et al. 2009). In addition, compounds such Ataluren (Peltz et al. 2013) that can also induce ribosomal read-through may prove efficacious.

The cytoplasmic N-terminal R298S mutation that is shared by all NBCe1 variants appears to be localized to a tightly folded region that has been hypothesized to form a “HCO3 tunnel” in the wild-type transporter but whose structure might be disrupted in the mutant (Igarashi et al. 1999; Horita et al. 2005; Chang et al. 2008; Suzuki et al. 2010; Zhu et al. 2010b). Moreover, Zhu et al. have suggested that the N-terminal and transmembrane regions of the transporter normally interact with each other and have hypothesized that in the mutant the efficient delivery of HCO3(and/or CO32−) to the ion permeation pathway is impaired (Zhu et al. 2013a). NBCe1-A appears to differ from AE1 in that the latter does not have a substrate access tunnel in its N-terminal cytoplasmic region (Shnitsar et al. 2013). An additional mechanism may be involved in that other groups have shown that when expressed in MDCK cells, the NBCe1-A R298S and corresponding NBCe1-B R342S mutants do not traffic to the basolateral plasma membrane preferentially but are expressed on the apical and basolateral membranes (Li et al. 2005; Suzuki et al. 2008) suggesting that a targeting signal in the N-terminal region has been perturbed. Gill et al. have reported that R298 forms part of a putative substrate conduit near the dimer interface that is held together by hydrogen-bond networks (Gill 2012). Moreover, it was proposed that the R298S mutation results in a temperature alteration of the monomer–dimer equilibrium that can expose charged surfaces resulting in protein aggregation and precipitation (Gill et al. 2015).

TM1–14 (Transmembrane Region)

TM1 which contains 31 amino acids and is longer than a standard TM has an N-terminal cytosolic portion with a helical conformation that connects the cytoplasmic portion with the transmembrane portion (Zhu et al. 2013a). The extracellular C-terminal end of TM1 forms a component of the ion permeation pathway where Thr442 which is located within a 441ITFGGLLG448 motif (NBCe1-A numbering) that is found in most SLC4 transporters is suggested to be part of an extracellular gate involved in ion entry (Zhu et al. 2009). TM1 contains several functionally important key residues that appear to line the ion permeation pathway including Ala428, Ala435 in addition to Thr442 (Zhu et al. 2009). Substituting of Asp416, Gln424, Tyr433, and Asn439 with cysteine causes misfolding of the transporter and intracellular retention. The cysteine scanning data are compatible with C-terminal end of TM1 having an open structure forming part of an aqueous-accessible cleft. These studies also revealed tight protein packing of the cytoplasmic pre-TM1 region.

The TM1 S427L pRTA mutation decreases transporter function by 90% resulting in pRTA. Of interest, the mutation also blocks the reversal of the direction of the transport current (Dinour et al. 2004). Ser427 has been localized to space-confined region in TM1 wherein the serine side chain hydrophobicity appears to be involved in helix packing and ionic interactions between helices (Zhu et al. 2013a). A conformational change in TM1 associated with a collapse/altered configuration of the ion permeation pathway has been hypothesized to be the cause of functional impairment associated with the S427L mutation. As in the R298S mutation, the S427L mutant when expressed in MDCK cells is mistargeted although in this instance, the mutant transporter is mislocalized to the apical membrane (Li et al. 2005).

Both the T485S mutation in intracellular loop 1 (IL1) and the adjacent G486R mutation in the beginning of TM3 independently cause pRTA (Horita et al. 2005; Suzuki et al. 2008, 2010; Zhu et al. 2010b, 2013b). Given the structural and chemical similarity between serine and threonine, the T485S mutation would not be predicted to cause pRTA and decrease overall base transport by approximately 50% (Horita et al. 2005; Suzuki et al. 2008, 2010; Zhu et al. 2010b, 2013b). Accordingly, Zhu et al. hypothesized that Thr485 must reside either in the aqueous ion permeation pathway or an ion interaction site (Zhu et al. 2013b). Thr485 was localized to an aqueous confined region, and the functional sensitivity to MTS reagents was substrate-dependent providing the first evidence that Thr485 is located in an ion interaction site. Whole cell patch clamp experiments of the wild-type transporter expressed in HEK-293 cells were compatible with NBCe1-A mediated electrogenic Na+-CO32− cotransport and a single anion interaction site (Zhu et al. 2013b). The T485S mutation converted NBCe1-A from an electrogenic to an electroneutral transporter compatible with the mutant mediating Na+-HCO3 cotransport (Zhu et al. 2013b). Using NO3 as a surrogate for CO32− transport, the T485S mutant unlike the wild-type transporter failed to mediate Na+-driven NO3 transport (Zhu et al. 2013b) suggesting that it favors HCO3 as a substrate. The adjacent G486R mutation was shown to perturb transporter function by altering the orientation of Thr485 (Zhu et al. 2013b).

In the context of the electroneutral T485S NBCe1-A pRTA mutation with an associated ∼50% decrease in transport activity, the proximal tubule basolateral membrane electrical potential is no longer a driving and given that the ion gradients are inward (basolateral to cytoplasm), the transporter will initially mediate inward Na+-base influx significantly impairing transepithelial bicarbonate absorption. Assuming that the threonine to serine substitution also decreases the functional activity of NBCe1-B/-C by ∼50% and converts these variants to electroneutral transporters, a decrease in their cellular base influx activity would be predicted. In addition, mutant NBCe1-B/-C transport would be potentially further perturbed by the decrease in the extracellular bicarbonate concentration (due to renal bicarbonate loss).

TM4, where the R510H, W516X, and L522P pRTA mutations are located, is reported to act as a scaffolding helix that is essential for normal protein folding (Zhu et al. 2010b). In addition, this helix has potential stop transfer and signal anchor sequences (Igarashi et al. 1999; Horita et al. 2005; Li et al. 2005; Demirci et al. 2006; Suzuki et al. 2008, 2010; Zhu et al. 2010b; Yamazaki et al. 2013). The W516X nonsense mutation truncates the transporter prematurely and likely results in misfolded protein (Lo et al. 2011). In W516X knock-in mice, prenatal Ataluren therapy (induces ribosomal read-through) significantly increased NBCe1 protein abundance and activity, and increased postnatal survival although prenatal bicarbonate administration achieved a higher survival rate (Fang et al. 2015). Similarly, both the R510H and L522P mutations induce misfolding and ER retention (Igarashi et al. 1999; Horita et al. 2005; Li et al. 2005; Demirci et al. 2006; Suzuki et al. 2008, 2010; Zhu et al. 2010b; Yamazaki et al. 2013). Why R510H causes protein misfolding is unclear; however, it is possible that the size of the side chain and/or magnitude of the positive charge at this position is required for the ionic interaction between TM4 and its neighboring TMs. Since L522I and L522C are processed to the plasma membrane normally (Zhu et al. 2010b; Yamazaki et al. 2013), the proline substitution at this position is the likely cause of increased TM flexibility resulting in helix disruption, protein misfolding, and intracellular ER retention.

Asp555 in TM5 appears to prevent several anions from being transported nonspecifically by NBCe1-A (Yang et al. 2009). When glutamate is substituted at Asp555, NBCe1-A also transports of Cl, NO3, and SCN in addition to electrogenic Na+-HCO3(CO32−) cotransport. The well-known stilbene inhibitor 4, 4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS) also interacts with residues in TM5 where the inhibitor binds from the transporter’s extracellular surface to a KKMIK motif (Lu and Boron 2007). It is currently unknown whether DIDS sterically blocks ionic interaction/permeation through the transporter or blocks ion transport by preventing substrate-induced conformational changes. At more positive membrane voltages, the apparent affinity between DIDS and NBCe1 is increased likely via voltage-dependent changes in transporter conformation (Yamaguchi and Ishikawa 2005; Lu and Boron 2007). DIDS is also able to inhibit the transporter function by interacting with an undermined intracellular binding site (Heyer et al. 1999). The site and mechanism of functional inhibition by other compounds including tenidap (Ducoudret et al. 2001), benzamil (Ducoudret et al. 2001), and S0859 (Ch’en et al. 2008) have not been investigated.

Two of the NBCe1 extracellular loops appear to play a structural/functional role. Located between TM5 and TM6, extracellular loop 3 (EL3) is the largest (83 amino acids) loop in NBCe1, a feature that is shared by other Na+-driven SLC4 transporters. The loop contains four cysteine residues that are intramolecularly disulfided that form a highly ordered domain-like structure that is glycosylated (Zhu et al. 2015). It has been hypothesized that this region in EL3 may bind a ligand(s) thereby regulating the function of the transporter analogous to the Cys-loop ligand-gated ion channel superfamily (Zhu et al. 2015). Extracellular loop 4 (EL4) located between TM7 and TM8 can interact with CAIX (Orlowski et al. 2012) and membrane bound CAIV (Alvarez et al. 2003). EL4 has also been reported to be involved in the ion transport stoichiometry and electrogenic properties of NBCe1 (Chen et al. 2011). Whether residues in EL4 are also involved in ion permeation/interaction thereby helping to determine the electrogenic properties of NBCe1 remains to be determined.

As shown in AE1 (Tang et al. 1999; Arakawa et al. 2015) TM8 was reported to also play an important role in NBCe1-A ion permeation (McAlear and Bevensee 2006). In a cysteine scanning study of TM8, the accessibility to pCMBS was altered by the presence of substrate ions and the stilbene inhibitor DNDS (4.4-dinitro-stilbene-2, 2′-disulfonate). Leu750 was found to be an important residue involved in ion permeation. It has recently been hypothesized that NBCe1-A- Asp754 interacts with Na+ and that loss of Arg730 in AE1 (replaced by Ile803 in TM10 of NBCe1-A) may be necessary to allow Na+ to permeate to its site of interaction (Reithmeier et al. 2016).

Deda et al. reported a patient with extrarenal K+ loss due to diarrhea and vomiting causing severe acute hypokalemia, who otherwise had with the same phenotype as other patients with NBCe1 mutations (Deda et al. 2001). The patient had a A799V EL5 pRTA mutation significantly decreasing mutant NBCe1-A function (Horita et al. 2005; Suzuki et al. 2010; Zhu et al. 2010b). Interestingly, the mutant transporter had an associated HCO3-independent cation leak conductance (Parker et al. 2012). Given the expression of NBCe1 in skeletal muscle (sarcolemma and possibly t-tubules) during severe acute hypokalemia, a patient with the A799V mutation would be predicted to develop exacerbated muscle weakness (Parker et al. 2012).

The R881C Helix loop 4 (HL4) pRTA mutation is another example where the plasma membrane expression Xenopus oocytes and mammalian cells differs (Horita et al. 2005; Toye et al. 2006; Suzuki et al. 2010; Zhu et al. 2010b). When expressed in Xenopus oocytes, the plasma membrane expression of the R881C mutant transporter is decreased (Horita et al. 2005; Toye et al. 2006). The R881C mutant when expressed in mammalian cells is retained in the ER likely due to misfolding (Zhu et al. 2010a). Importantly, the loss of functional activity appears to be entirely due to abnormal plasma membrane localization (Toye et al. 2006).

Chen et al. using a TM swapping approach reported that TM6 and TM12 in their topology model form a “functional unit” that plays a role in plasma membrane localization (Chen et al. 2012). In these experiments, a chimera was made with TM6 and what was referred to as “TM12” by replacing these TMs with corresponding TMs from electroneutral NBCn1. Although plasma membrane processing was significantly decreased, the interpretation of the data is more complicated since residues from TM12, intracellular loop 6 (IL6), and TM13 were also swapped based on our most studied topological model (Zhu et al. 2015) rather than TM12 alone (Fig. 4). In particular, mixed chimeras per se can potentially fold improperly resulting in ER retention (Fujinaga et al. 2003) and residues in TM12 may play a role in helix packing (Zhu et al. 2010a).

Rather than TM12 alone, the entire C-terminal transmembrane region from TM10–14 appears to play an important role in helix packing and protein folding (Zhu et al. 2010a). The structure of NBCe1 is stabilized by residues clustered on the surface of the protein that form intramolecular hydrogen bonds. The loops connecting TMs11–14 are not exposed to the aqueous but rather are tightly folded in the protein. Met858 is bracketed by Pro857 and Pro858 and is the amino acid residue where TM12 bends abruptly into the lipid bilayer. Lys924 in TM13 likely contributes to helix packing by acting as a counter ion. Extracellular loop 7 (EL7; Thr926-Ala929) is minimally exposed to the aqueous media suggesting it is tightly folded in the transmembrane region (Zhu et al. 2010a).

A patient with the first compound heterozygous NBCe1 mutation (R510H/Q913R) was recently reported (Myers et al. 2016). The Q913R mutation was localized intracellularly as was a previously reported Q913C substitution in TM13 likely to due to protein misfolding (Abuladze et al. 2005). In Xenopus oocytes, the mutant protein had normal activity but was associated with a HCO3 independent anion-leak whose clinical significance is unclear.

C-Terminal Cytoplasmic Tail

The C-terminal cytoplasmic tails belonging to each monomer in the NBCe1 dimer have stretches of strongly charged amino acids that may form a regulatory motif (Zhu et al. 2010a). Although the role(s) of the C-terminal tail is not precisely defined, there is evidence suggesting that it plays a role in membrane processing and targeting in that a 65 bp-del frame shift mutation causing pRTA truncates the C-terminal tail and in mammalian cells the mutated protein is retained in the ER (although not in Xenopus oocytes) (Suzuki et al. 2010). Furthermore, studies in MDCK cells suggest that a 1010QQPFLSP1015 motif in the C-terminal tail functions as a basolateral targeting signal (Li et al. 2004).

Comparison of NBCe1 and AE1

The determination of the crystal structure of transmembrane region of the human AE1 dimer allows homology models of other SLC4 transporters based on sequence similarity to be generated (Arakawa et al. 2015; Reithmeier et al. 2016). NBCe1 has the identical predicted 7 + 7 topology as AE1 that is predicted given their sequence similarity. While AE1, AE2, and AE3 have a conserved Glu681 that acts as a H+ binding site in AE1 required for sulfate transport, in NBCe1, Asp754 is the homologous residue that potentially helps coordinate Na+ (Reithmeier et al. 2016) Fig. 5).
NBCe1 Electrogenic Na+-Coupled HCO3−(CO32−) Transporter, Fig. 5

Predicted NBCe1-A site for ion coordination (modified from Reithmeier et al. 2016) based on homology with the crystalized transmembrane region of AE1 (Arakawa et al. 2015; Reithmeier et al. 2016)

Cysteine scanning mutagenesis studies have detailed additional differences in their topologic features, which likely reflects their functional properties differences and molecular mechanisms of ion transport. These differences are in keeping with the well-characterized differences in the atomic structure of prokaryotic ion exchangers versus Na+-coupled substrate transporters. The structural differences between NBCe1-A and AE1 likely play an important role in different functional properties and ion substrate affinities. In NBCe1-A, for example, TM1 has been shown to play a role in forming part of the ion translocation pathway and residues in TM1 interact tightly with the cytoplasmic region (Zhu et al. 2009). The AE1-TM1, however, does not appear to be involved in ion permeation and the AE1 N-terminal cytoplasmic region does not appear to form a substrate access tunnel as in NBCe1-A (Shnitsar et al. 2013). In NBCe1-A, the large extracellular loop (EL3) is intradisulfided unlike AE1 and resistant to enzymatic digestion suggesting it is tightly folded and has been hypothesized to play an important a role in ligand binding (Zhu et al. 2015). The transmembrane region of NBCe1-A does not appear to have the reentrant loops that were previously reported in AE1 (Zhu et al. 2003; Zhu et al. 2010a). In NBCe1-A TMs13 and 14 are not involved in ion translocation as has been reported in AE1 (Zhu and Casey 2004; Zhu et al. 2010a).

NBCe1 Regulation

Intrinsic Autoregulatory Features

The structural differences in the N-terminal and/or C-terminal regions of the NBCe1 variants allow variant-specific functional regulation with various cytoplasmic factors. McAlear et al. first reported that NBCe1-A N-terminus functions as an autostimulatory domain (ASD). How the ASD enhances NBCe1-A function remains unknown (McAlear et al. 2006). NBCe1-D has the same extreme N-terminal sequence and it would be of interest to determine its role as an ASD in this variant. Zhu et al. reported evidence for interaction between the transmembrane region and the NBCe1-A N-terminus (Zhu et al. 2013a). The functional relevance of this finding and whether the autostimulation of the transporter required interaction of specific residues in the extreme N-terminus with the intracellular transmembrane region requires further study. Unlike the NBCe1-A ASD, the identical N-terminus of NBCe1-B and NBCe1-C (and presumably the NBCe1–E variant) functions as an autoinhibitory domain (AID) (McAlear et al. 2006; Lee et al. 2012). The C-terminus in NBCe1-C may also either function as a separate AID or contribute to the N-terminal AID.

IRBIT

The second messenger IRBIT binds to the IP3 receptor (Ando et al. 2003) and when released from the receptor regulates ion channels and transporters (Ando et al. 2014). IRBIT stimulates NBCe1-B and NBCe1-C but not NBCe1- A (Shirakabe et al. 2006). Various residues/regions within the NBCe1-B N-terminus has been reported to contribute to IRBIT binding/regulation including: amino acids 1–18 and 37–62 (Shirakabe et al. 2006); an RRR motif (42–44) in the positively charged 37–65 region (Hong et al. 2013); T49 (Hong et al. 2013); and residues 4–16 (Lee et al. 2012; Seki et al. 2008) initially suggested that IRBIT functions by masking the NBCe1-B AID inhibition. Protein phosphatase-1 (PP-1) binds to IRBIT and blocks its stimulation of NBCe1-B function (Devogelaere et al. 2007). Using a mutated IRBIT that does not bind PP-1 (Lee et al. 2012) showed that the function of NBCe1-B coexpressed with the mutated IRBIT was greater than an N- terminally truncated NBCe1-B mutant lacking the N-terminal AID (Lee et al. 2012) suggesting that a mechanism in addition to masking the AID must underlie the effect of IRBIT.

WNK/SPAK

The WNK (with-no-lysine kinase)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) pathway (Yang et al. 2011) inhibits NBCe1-B (Yang et al. 2011; Hong et al. 2013). WNK does not act as a kinase per se but binds to SPAK which phosphorylates Ser65 decreasing the plasma membrane expression of the transporter (Hong et al. 2013). The recruitment of protein phosphatase 1 (PP-1) by IRBIT counters the WNK/SPAK inhibition of the transporter (Yang et al. 2011; Lee et al. 2012; Hong et al. 2013). The phosphorylation of NBCe1-B-Thr49 that has previously been show to increase transporter activity (Gross et al. 2003) is required for both IRBIT and WNK/SPAK pathway regulation of the transporter (Hong et al. 2013). IRBIT and PIP2 (see below) may compete for the same binding N-terminal site (positively charged N terminal region 37–65) (Hong et al. 2013). Whether IRBIT modulates NBCe1-B function via a change in plasma membrane expression likely depends on the cell type and specifically the activity of the endogenous WNK/SPAK pathway (Shirakabe et al. 2006; Lee et al. 2012; Yang et al. 2011).

Additional Factors Affecting the NBCe1 Phosphorylation State: AII, PKC, PKA/cAMP, ATP, and Src Kinase

The phosphorylation state of NBCe1 affects both its functional properties and plasma membrane localization. ANG II has a dose-dependent biphasic effect on NBCe1 function (Coppola and Frömter 1994a, b; Horita et al. 2002; Zheng et al. 2003; Perry et al. 2006). Mediated through AT1B receptors, the inhibition of NBCe1-A via ANG II is mediated by Ca2+−-insensitive PKCε leading to decreased NBCe1-A plasma membrane localization (Perry et al. 2006, 2007). In experiments in Xenopus oocytes expressing NBCe1-A, Ca2+ shifts the ion transport stoichiometry from 1:2 to 1:3 that may be mediated by a change in PKC-dependent phosphorylation of the transporter (Muller-Berger et al. 2001). It has also been reported that PKA-dependent phosphorylation of NBCe1-A-Ser982 shifts the ion transport stoichiometry in the opposite direction from 1:3 to 1:2 (Gross et al. 2001c). In the extreme NBCe1-B N-terminus, cAMP-induced phosphorylation of Thr49 increases transport without altering the ion transport stoichiometry (Gross et al. 2003). In addition, cAMP has also been reported to increase intestinal NBCe1-B function in part because of an increase in plasma membrane localization (Bachmann et al. 2003; Yu et al. 2009). A decrease in plasma membrane localization of both NBCe1-A and NBCe1-B is induced by both PKCs (PKCαβγ) and a novel PKCδ that participate in the constitutive and stimulated (carbachol) mediated endocytosis of the transporters (Perry et al. 2009) providing an additional modulatory pathway in salivary duct, ileum, and colon (Bartolo et al. 2009; Perry et al. 2009; Yu et al. 2009). In addition to phosphorylation via PKCs, it has been suggested that ATP can phosphorylate NBCe1-A via an as yet undefined protein kinase increasing transporter function (Muller-Berger et al. 2001). In submandibular glands, acute intracellular acidification stimulates NBCe1-B phosphorylation via Src kinase that results in increased plasma membrane localization of the transporter (Namkoong et al. 2015).

PIP2; PIPKIα

PIP2 activation of NBCe1-B and NBCe1-C involves a staurosporine-sensitive kinase (Thornell et al. 2012; Thornell and Bevensee 2015). PIP2 also prevents the rundown of NBCe1-A in oocyte macropatches (and potentially NBCe1-D) (Wu et al. 2009). Hong et al. (2013) suggested that PIP2 and IRBIT compete for a polycationic site arginines (42–44) in the NBCe1-B N-terminus. The exact PIP2 binding site(s) in NBCe1 is unknown and there are additional cationic stretches in common to NBCe1 transporters where PIP2 may bind.

It has recently been shown that IRBIT forms a signaling complex with members of the PIPK family that includes PIPK type Iα (PIPKIα) and type IIα (PIPKIIα) (Ando et al. 2015). Phosphatidylinositol 4-phosphate, Mg2+, and/or ATP interfere with this interaction and binding experiments showed that IRBIT, PIPKIα, and NBCe1-B form a tertiary complex. The complex with PIPKIα is hypothesized to modulate the activity of NBCe1-B through changes in the local production of PIP2.

Calcium/IP3

In Xenopus oocytes PIP2 stimulation of NBCe1-B and NBCe1-C requires its hydrolysis to IP3 (Thornell et al. 2012). The function of NBCe1-B and NBCe1-C and not NBCe1-A is increased by a rise in intracellular Ca2+ (Thornell et al. 2012) that may be mediated through the N-terminal AID. An increase in intracellular Ca2+ by activating endogenous oocyte Gq-coupled receptors increases NBCe1-B expression and NBCe1-C function (Thornell et al. 2012). An increase in bath calcium in oocyte macropatch membranes (intracellular surface) shifted the charge transport stoichiometry from 1:2 to 1:3 (Muller-Berger et al. 2001).

Magnesium

Intracellular Mg2+ can inhibit of NBCe1-B function (Yamaguchi and Ishikawa 2008, 2012) and potentially NBCe1-C/−E. The effect may be mediated by the N-terminal AID, however, it is currently unknown whether Mg2+ and IRBIT compete for a common binding site or act independently. When expressed in Xenopus oocytes, Mg2+ induced NBCe1-A functional rundown via a mechanism that has been hypothesized to potentially be mediated by a Mg2+-dependent phosphatase (5′-lipid phosphatase) that involved the dephosphorylation of PIP2 to PIP (Wu et al. 2009). Mg2+ may also block the interaction of PIP2 with the transporter which is compatible with the finding that polyvalent cations decrease the inhibitory effect of Mg2+ on NBCe1-A and NBCe1-B function (Yamaguchi and Ishikawa 2008; Yamaguchi and Ishikawa 2012; Wu et al. 2009). During an ischemic insult, inhibition of NBCe1 function by an elevation of intracellular Mg2+ may reduce cellular dysfunction perhaps via a change in intracellular Na+ and/or pH (Wu et al. 2009).

Chloride

Intracellular Cl regulates NBCe1-B transport via two GXXXP-containing sites and regulation of NBCe1-A is mediated via single cryptic GXXXP motif (Shcheynikov et al. 2015). Under basal conditions, NBCe1-B is inhibited by a high Cl concentration via interaction with the low affinity GXXXP site, and IRBIT activation of NBCe1-B unmasks a second high affinity Cl interacting GXXXP site. Changes in Cl concentration between 5 and 140 mM have no effect on NBCe1-A activity and deletion of residues 29–41 unmasked the cryptic GXXXP site that mediates the Cl-dependent inhibition of NBCe1-A activity.

Carbonic Anhydrase

CA inhibition was shown to reduce the activity of NBCe1-A operating with 1:3 but not a 1:2 charge transport stoichiometry (Gross et al. 2002). In pull-down studies, the magnitude of acetazolamide mediated inhibition of NBCe1-A was shown to vary with the degree of CAII/NBCe1-A binding. C-terminal NBCe1-A 958LDDV961 and 986DNND989 motifs were proposed to be part of a single binding site (Pushkin et al. 2004). Using isothermal titration calorimetry, Gross et al. proposed that NBCe1 and cytoplasmic CAII interact at a high affinity biding site (160 nM) to form a transport metabolon (Gross et al. 2002). Alvarez et al. showed that expression of a catalytically impaired CAII mutant resulted decreased NBCe1-B function (Alvarez et al. 2003). Further studies in Xenopus oocyte expression systems provided additional support for interaction between CAII and NBCe1 (Pushkin et al. 2004; Becker and Deitmer 2007). Membrane-associated CAIV and CAIX were subsequently shown to interact with the extracellular surface of NBCe1-B at EL4 (dependent on Gly767) (Alvarez et al. 2003; Orlowski et al. 2012). Other studies were unable to demonstrate a functional interaction between NBCe1 and CAII (Lu et al. 2006; Piermarini et al. 2007; Yamada et al. 2011). Differences in techniques/preparations used among the various assays employed in these studies may account for the various findings reported. Mice with targeted disruption of CAII and patients’ loss of function mutations in CAII do not have a severe proximal tubule bicarbonate wasting phenotype (Sly et al. 1985; Lewis et al. 1988). The finding that loss of CAII function results in a milder phenotype than loss of NBCe1 function in patients suggests that even if a functional coupling between CA proteins and NBCe1 exists in vivo, the interaction does not appear to be clinically significant. Moreover, patients with CAIV mutations do not have pRTA but instead have an ocular phenotype due to retinitis pigmentosa (RP17) (Rebello et al. 2004). Schueler reexamined the interaction between CA enzymes and NBCe1-A in Xenopus oocytes and showed that CAI, CAII, and CAIII stimulate NBCe1-A function that was mediated through carbonic anhydrase enzymatic activity and not intramolecular proton shuttling (Schueler et al. 2011).

STCH

In NBCe1-B, sp70-like stress 70 protein chaperone STCH interacts with residues 96–440 (distal to IRBIT interaction) inducing a significant increase in plasma membrane localization (Bae et al. 2013). Whether STCH also increases the plasma membrane expression of other variants is not known. Increased STCH-induced NBCe1-B plasma membrane localization may represent a novel regulatory pathway that certain cells possess to prevent cellular dysfunction during metabolic acidosis by increasing their ability to regulate intracellular pH more efficiently (Bae et al. 2013).

Hormonal Factors and Systemic Blood Pressure

PTH, dopamine, norepinephrine, and potentially changes in systemic blood pressure have been shown to modulate the expression of NBCe1. Specifically, PTH decreases NBCe1 activity in rats possibly via cAMP, whereas there is no effect on NBCe1 function in rabbits (Sasaki and Marumo 1991). Dopamine decreases NBCe1-A activity in rat and rabbit proximal tubules (Kunimi et al. 2000). In rats, chronic infusion of noradrenaline increases NBCe1 expression (Sonalker et al. 2008). In the SHR rat, NBCe1 protein expression is increased approximately twofold in comparison to control WKY rats (Sonalker et al. 2004); however, the causal relationships in this model are unknown.

Blood Chemistry Changes

Both NaHCO3 and NaCl administration decrease the expression of NHE3 and NBCe1-A in the proximal tubule (Amlal et al. 2001). The change in NBCe1-A expression provides a potential mechanism for ameliorating metabolic alkalosis by increasing renal bicarbonate excretion, and volume overload by increasing renal Na+ excretion. K+ depletion that is associated with metabolic alkalosis is accompanied by an increase in proximal tubule bicarbonate reabsorption (Roberts et al. 1955; Rector et al. 1964; Capasso et al. 1987). The latter finding is potentially due to increased proximal tubule expression of NBCe1-A (Amlal et al. 2000).

Miscellaneous Systemic Diseases

In a model of renal transplant rejection in rats, the expression of NBCe1-A is increased (Velic et al. 2004); however, NBCe1-A expression is decreased by the calcineurin inhibitor FK506 (Mohebbi et al. 2009). In lithium-induced distal renal tubular acidosis (dRTA), NBCe1-A expression is upregulated perhaps as a compensatory mechanism that increases proximal tubule bicarbonate reabsorption (Kim et al. 2003). In a ureteral obstruction model of hyperkalemic dRTA, NBCe1-A expression in the proximal tubule is decreased (Wang et al. 2008). Hypothyroidism in humans can be associated with incomplete dRTA, and in a hypothyroid model in rats, decreased NBCe1 abundance has been reported (Mohebbi et al. 2007). Concomitant NH4Cl loading in hypothyroid rats increases NBCe1 expression (Mohebbi et al. 2007).

Summary

The present review summarizes our current understanding of the structure-function properties and regulation of the electrogenic sodium bicarbonate cotransporter NBCe1. NBCe1 encoded by the SLC4A4 gene belongs to the SLC4 gene transporter family which share amino acid sequence homology and in general couple the transport of HCO3 (and/or CO32−) to Na+ and/or Cl. The mammalian SLC4A4 gene encodes five NBCe1 variants (NBCe1-A-E) that share an identical plasma membrane region but differ in the sequence of their cytoplasmic N- and C-termini. Mutations in the transporter cause the kidney disease proximal renal tubular acidosis (pRTA) with associated neurologic and ocular abnormalities. These mutations prevent both normal plasma membrane targeting and/or alter the functional properties of NBCe1. This review highlights the structure-function properties and regulation of NBCe1, and its role in cellular acid-base physiology in health and disease.

Notes

Acknowledgments

Dr. Kurtz is supported in part by funds from the NIH (R01-DK077162), the Allan Smidt Charitable Fund, the Factor Family Foundation Chair in Nephrology, and the Arvey Foundation.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of NephrologyDavid Geffen School of Medicine, and Brain Research InstituteLos AngelesUSA