SLC4 Sodium-Driven Bicarbonate Transporters

In this chapter, while extra-renal studies will be highlighted, an emphasis will be placed on the biology of specific sodium-coupled SLC4 proteins in the kidney.

Key Words

SLC4, bicarbonate, kidney, renal tubular acidosis, sodium, transport, acid–base, pH

The SLC4 ( s o l ute c arrier 4) family is a group of a membrane proteins that share sequence homology and in general mediate the transport of bicarbonate. It should be noted that bicarbonate transport is not unique to the SLC4 family. The structurally unrelated SLC26 family has at least three proteins that mediate Cl−HCO−3
Cl − HCO 3 −
exchange. In this chapter, the biology of SLC4 Na ⁺ -dependent bicarbonate transporters will be highlighted. The outlier in the SLC4 family is the SLC4A11 gene product (NaBC1) that lacks the ability to transport bicarbonate and is currently characterized as an electrogenic sodium-borate transporter. Whether SLC4 transporters mediate bicarbonate and/or carbonate transport is unclear and therefore when the word bicarbonate or the chemical symbol HCO−3
HCO 3 −
is used throughout the chapter with reference to SLC4 mediated ion transport, it refers to both HCO−3
HCO 3 −
and/or CO2−3
CO 3 2 −
.

In this chapter, while extra-renal studies will be highlighted, an emphasis will be placed on the biology of specific sodium-coupled SLC4 proteins in the kidney.

Functional Categorization of the SLC4 Family

A dendrogram of the SLC4 family of proteins is shown in Fig. 53.1 . The 10 different SLC4 gene products can be logically subdivided functionally and structurally into four groups that differ primarily in their Na ⁺– and Cl ⁻-dependence and electrogenic properties. Although various categorizations have been proposed, the following is a convenient scheme:

Na ⁺-independent ??−Unknown node type: glyphHC?−3
C l − HC O 3 −
exchangers: 3 homologous transporters, AE1, AE2, and AE3 ( SLC4A1, -2,-3 respectively) that mediate Cl––HCO−3
Cl – – HCO 3 −
exchange have been well characterized. A fourth member, AE4, has also been reported to function as a Cl––HCO−3
Cl – – HCO 3 −
exchanger. However, as will be discussed, the amino acid sequence of AE4 is more homologous to sodium-coupled SLC4 transporters.

??+Unknown node type: glyphHC?−3
N a + HC O 3 −
cotransporters: There are 3 well-characterized members of the SLC4 family that transport Na ⁺and HCO−3
HCO 3 −
without concomitant net Cl ⁻transport. NBCe1 ( SLC4A4 gene) and NBCe2 ( SLC4A5 gene) are sodium bicarbonate cotransporters that are chloride-independent and electrogenic in that their HCO−3
HCO 3 −
to Na ⁺transport coupling is >1 (2:1, or 3:1). NBCn1 ( SLC4A7 gene) is an electroneutral Na+Unknown node type: glyphHCO−3
Na + HCO 3 −
cotransporter with a coupling ratio of 1:1.

Na ⁺-driven ??−Unknown node type: glyphHC?−3
C l − HC O 3 −
exchangers: Two SLC4 transporters have been reported to mediate Na+Unknown node type: glyphHCO−3
Na + HCO 3 −
cotransport in exchange for chloride. The literature regarding the functional properties of the first reported mammalian transporter, NCBE (SLC4A10), is somewhat confusing. Although this transporter is reported by several groups to mediate Na ⁺-dependent Cl−Unknown node type: glyphHCO−3
Cl − HCO 3 −
exchange, a separate study in oocytes has shown that chloride is not transported under physiologic conditions, and accordingly the protein was renamed NBCn2 ( Na+–HCO−3
Na + – HCO 3 −
cotransporter electroneutral 2). The details of the discrepant findings in this area are discussed below. The second reported transporter in this group, NDCBE ( SLC4A8 gene), is a well-characterized Na ⁺-driven Cl−–HCO−3
Cl − – HCO 3 −
exchanger.

Electrogenic Na-borate cotransporter: NaBC1 has been reported to mediate the electrogenic transport of Na+–BO–4
Na + – BO 4 –
in the presence of borate, or Na ⁺OH ⁻cotransport with coupling ratio of Na ⁺:anion of at least 2 (electrogenic) in the absence of borate. The lack of a clear role for borate transport in various tissues where this transporter is expressed raises questions regarding the actual function of NaBC1 physiologically.

Several SLC4 transporters expressed in the kidney have been localized at the transcript/or protein level in various nephron segments and cell types ( Tables 53.1–53.3 ; Fig. 53.2 ). Studies involving the expression of SLC4 transcripts in the kidney have been done in several mammalian species including mouse, rat, rabbit and human. In addition to documented known species differences, SLC4 proteins typically have a number of specific variants (due to splicing and/or alternate promoter usage) whose localization in the kidney and functional properties have not been thus far thoroughly investigated. This fact increases significantly the complexity of addressing the actual protein expression pattern and functional characteristics of each SLC4 transporter in various renal cell types.

Table 53.1

Immunolocalization of Na ⁺-driven SLC4 Transporters in Kidney

Transporter	Location	Apical	Basolateral	Human	Rat	Mouse
NBCe1	PT		+	+	+	+
NBCe2	OMCD	N/A	N/A	+
	P(U)	+		+
NBCn1	mTAL		+	+	+
	OMCD–αIC		+
	IMCD 2 & 3		+
	P(U) *				+
NaBC1 **	Podocytes			+	+
	PT	+	+	+	+
	tDL		+		+	+ ****
	CCD – IC ***	+		+
	OMCD – IC ***	+		+
	IMCD		+	+

PT – proximal tubule.

OMCD – outer medullary collecting duct.

P(U) – pelvis (uroepithelium).

tDL – thin descending limb.

mTAL – medullary thin descending limb.

IMCD – inner medullary collecting duct.

* LacZ staining.

** NaBC1 does not transport Na bicarbonate.

*** IC type not specified.

**** immunolocalization and LacZ staining only in the tDL in mouse.

Table 53.2

SLC4 Na ⁺-driven Transporters that Have Not Been Immunolocalized in Kidney

Transporters	Technique	Location	Human	Rat	Mouse
NCBE/NBCn2	Northern: weak		+
NDCBE	Northern: weak		+
	RT-PCR	cortex (weak), medulla	+
	RT-PCR	inner medulla		+
	Western	cortex/CCD			+

Table 53.3

AE4 Immunolocalization in the Kidney

Location	Apical	Basolateral	Rat	Mouse	Rabbit
CCD: βIC	+				+
CCD: αIC	+	+			+
CCD: αIC, βIC		+	+
CCD: βIC		+		+

The kidney and brain share the property of having various cell types that express different bicarbonate transporter proteins. Although most SLC4 transporters have in common the property of transporting bicarbonate, cells in the kidney and brain are likely taking advantage of the unique and specific properties of each transporter. The uniqueness of SLC4 proteins stems from the fact that these transporters differ significantly in their ion (Na ⁺, Cl ⁻) dependence, coupling ratios, membrane targeting, substrate affinities, developmental expression, regulation by factors pH/phosphorylation, and protein-protein interaction. These differences also account for the fact that functionally, SLC4 transporters have various direct and indirect physiological roles in the kidney including transepithelial bicarbonate transport, intracellular pH regulation, and transport of Cl ⁻, Na ⁺and possibly NH ₄⁺.

Because SLC4 transporters are expressed not only in the kidney but also in various extrarenal organs and cell types, diseases associated with mutations in these transporters or targeted disruption in mice result in both a renal and extrarenal phenotype ( Table 53.4 ).

Table 53.4

Phenotype with Altered SLC4 Function

Transporter	Human	Mouse
NBCe1	pRTA	pRTA
	band keratopathy	intestine obstruction
	glaucoma, cataracts	spleen abnormalities
	intracerebral calcification	enamel defect
	enamel defect
	↑ amylase, ↑ lipase
NBCe2	hypertension	hyperchloremic metabolic acidosis
		hyporeninemic hypoaldosteronism
		hypertension
NBCn1		Usher 2B- like syndrome
NDCBE		↓ CCD electroneutral NaCl transport
NCBE/NBCn2	↑ seizure propensity	↓ cerebral ventricle size
NCBE/NBCn2		↓seizure threshold
NaBC1	CHED2; Harboyan Syndrome; FECD	CHED2 – like
	CHED2; Harboyan Syndrome; FECD	↓ urine osmolarity
		↑urine volume
		↑excretion of Na ⁺, K ⁺, Cl ⁻, Mg ²⁺
		↓ urinary [Ca ²⁺]
AE4		no phenotype

Sodium Bicarbonate Cotransporters (Electrogenic)

NBCe1 (SLC4A4 Gene)

Structural Variants

Our knowledge regarding the structure of sodium-dependant SLC4 transporters has until recently been extrapolated from the large body of data obtained from studies on the AE1 anion exchanger. More recent studies of NBCe1 reveal very interesting structural and functional differences from AE1. Three variants of the SLC4A5 gene have been well characterized. All three NBCe1 variants mediate electrogenic Na+–HCO−3
Na + – HCO 3 −
cotransport, but differ in their N- and C-terminal extremities, regulation, and intrinsic activity. In kidney, NBCe1-A (or kNBC1) is predominantly expressed in S1 and S2 proximal tubule cells where it mediates the basolateral efflux of HCO−3
HCO 3 −
, thereby contributing to the reabsorption of ~80% of the filtered bicarbonate load. In addition to the proximal tubule, NBCe1-A is also expressed in the eye and salivary gland. NBCe1-A transcripts have also been detected in nasal submucosal glands in turbinate mucosa and nasal polyps.

The second NBCe1 variant, NBCe1-B (or pNBC1), which is identical to NBCe1-A except for its unique N-terminus (85 aa replacing the 41 aa in NBCe1-A) was originally cloned from pancreas and is expressed in pancreatic duct epithelial cells where it contributes to basolateral bicarbonate flux from blood to cell, during the process of secretin-evoked pancreatic fluid secretion. NBCe1-B is also widely expressed in various other tissues including, colon, skeletal muscle, eye, airway submucosal glands, heart, gall bladder, and nasal mucosa. The third variant, NBCe1-C, has a unique C terminus (61 aa replaces 46 in NBCe1-A or B) that ends in a type I PDZ-binding motif. The N-termini of NBCe1-B and NBCe1-C are identical and unlike the N-terminus of NBCe1-A, interact with the IP3 receptor binding protein IRBIT resulting in a stimulation of transport activity. More recently additional transcript have been reported.

Topological and Structural Properties

Of the NBCe1 variants, the structural topology of NBCe1-A has been most thoroughly studied and provides a topologic framework for other Na ⁺-driven SLC4 bicarbonate transporters ( Fig. 53.3 ). NBCe1-A is an oligomer wherein the predominant oligomeric state of the cotransporter is dimeric. The NBCe1-A monomer is a ~140-kDa glycoprotein containing 1035 amino acids and is composed of 14 transmembrane regions (TMs). The N-terminal transmembrane region has 8 TMs homologous to the SLC4 transporter AE1. Both the extreme N- and C-termini of NBCe1-A are located in cytoplasm, with a large extracellular loop between transmembrane segment (TM) 5 and 6 containing two glycosylation sites. Importantly, although NBCe1-A forms a structural oligomer, each monomeric subunit maintains its own independent transport activity.

Previous topological models of NBCe1 were based on the assumption that the cotransporter resembles AE1 which has been extensively studied structurally. The C-terminal transmembrane region of the two transporters share 40% sequence homology but differ structurally. NBCe1-A lacks the two AE1 reentrant loops and extensive substituted cysteine scanning mutagenesis analysis showed that the C-terminal transmembrane region of NBCe1-A is tightly folded unlike AE1 resembling in various aspects the bacterial Na ⁺-leucine cotransporter, LeuT.

An extensive mutatgenesis study of NBCe1-A has demonstrated several key residues that are critical for its function. Domain swapping studies of the cotransporter have also shed light on its functional properties and have suggested the electrogenicity of NBCe1-A is determined by the interaction of TMs in the lipid bilayer. Arg ²⁹⁸in the N-terminus may be involved in constructing a “ HCO−3
HCO 3 −
tunnel”. Residue Thr ⁴⁴²in TM 1 is thought to form an external gate for the transported ions. Proposed TM8 has several residues found to be involved in forming the ion translocation pore. Interestingly, substitution of Asp ⁵⁵⁵to glutamic acid in the proposed TM 5 of NBCe1-A induced an outward rectifying Cl ⁻current and altered the transport substrate selectivity, indicating it plays an important role in HCO−3
HCO 3 −
selectivity.

Inhibitors

Asp ⁵⁵⁵is in close proximity of the proposed 4,4’-diisothiocyanatostilbene-2,2’-disulfonate DIDS (a functional inhibitor) binding site of NBCe1-A (Lys ⁵⁵⁹). From the extracellular side, DIDS blocks NBCe1 reversibly by binding to a KKMIK motif at the putative extracellular end of TM5. The apparent affinity of the interaction decreases at more negative voltages possibly due to alterations in the conformation of the cotransporter as the membrane voltage changes. DIDS is also capable of blocking the cotransporter from the intracellular side at an unknown site. In addition to DIDS, NBCe1-A is also blocked by the nonsteroidal inflammatory agent Tenidap from the extracellular or intracellular side. NBCe1-B is sensitive to the anion channel inhibitors phloretin, niflumic acid, NPPB, and glybenclamide. NBCe1 is inhibited by the N-cyanosulphonamide compound S0859 however the inhibition is not specific. Benzamil has also been reported to inhibit NBCe1-A.

Familial Proximal Renal Tubular Acidosis: Molecular Mechanisms Involving NBCe1

Patients with autosomal recessive mutations in NBCe1 have an unique phenotype that can be diagnosed clinically that includes severe hyperchloremic acidosis, with extra-renal manifestations including growth and mental retardation, basal ganglia calcification, cataracts, corneal opacities (band keratopathy), glaucoma, elevated serum amylase and lipase, and defects in the enamel consistent with amelogenesis imperfecta. Regarding the renal phenotype, this “experiment of nature” demonstrates the importance of NBCe1-A in mediating proximal tubule bicarbonate reclamation; the extrarenal manifestations demonstrate the importance of NBCe1- variants in eye (NBCe1-A, NBCe1-B; ), brain (NBCe1-B, NBCe1-C; ), and tooth ameloblasts (NBCe1-B; ). Thus far, the following mutants have been described: eight missense mutations (R298S, S427L, T485S, G486R, R510H, L522P, A799V, and R881C), 2 nonsense mutations (Q29X, W516X), a frameshift deletion at nucleotide 2311A, and a C-terminal 65 base-pair deletion from exon 23 to intron 23 predicted to truncate the intracytoplasmic C-terminus ( Fig. 53.3 , Table 53.5 ). Other than the NBCe1-A-Q29X mutation which only affects NBCe1-A, the NBCe1-B and -C variants are also mutated resulting in the extrarenal manifestations in this disorder.

Table 53.5

SLC4A4 Mutations: Molecular Mechanisms

Mutation	Location	Effect	Mechanism
Q29X *	N-terminus	truncation	—
R298S	N-terminus	↓ function	ion permeation pathway
S427L	TM1	↓ function	voltage sensing
T485S	TM3	↓ function	protein conformation
G486R	TM3	↓ function	protein conformation
R510H	TM4	misfolding	ER retention
W516X	TM4	truncation	—
L522P	TM4	misfolding	ER retention
2311delA	IL4	truncation	—
A799V	TM10	↓ function	protein conformation
R881C	TM12	misfolding	ER retention
65bp-del	C-terminus	truncation	—

TM Transmembrane

IL Intracellular Loop

* NBCe1-A only

The disease causing mechanism of the nonsense/frameshift mutations is due to absence of the full-length NBCe1 protein, whereas the missense mutations result from either reduced transport function and/or impaired plasma membrane processing (R510H, L522P, and R881C; (53, 114, 122)). The functional and targeting defects caused by NBCe1-A pRTA missense mutations have been analyzed in Xenopus oocyte, ECV304 cells, Madin-Darby canine kidney cells, and HEK293 cells with sometimes differing results. In general, mutant membrane transporter proteins are thought to have reduced function as a result of three possible mechanisms that are not mutually exclusive: (1) misfolding of the transporter protein resulting in ER retention; (2) alteration of the ion translocation (permeation) pathway; and (3) impairment of the transporter conformation (static/dynamic) required for substrate translocation.

Missense Mutations

Recent studies have focused on the topologic/structural/functional implications of the residues in NBCe1 that are mutated in pRTA ; ( Table 53.5 ). Arg ²⁹⁸is located in the cytoplasmic N-terminus of NBCe1-A and resides in a tightly folded aqueous inaccessible conformation based on: (1) homology modeling to the crystallized cytoplasmic domain structure of AE1 and (2) biotin maleimide labeling assays. It has been suggested that Arg ²⁹⁸may be involved in constructing a “ HCO−3
HCO 3 −
tunnel” in NBCe1-A and that mutation R298S disrupts the local structure of the ion permeation pathway thereby impairing the HCO−3
HCO 3 −
entry. The remaining missence pRTA residues have recently been localized in the transporter ( Fig. 53.3 ): Ser ⁴²⁷to TM 1, Thr ⁴⁸⁵, Gly ⁴⁸⁶to TM 3, Arg ⁵¹⁰and Leu ⁵²²to TM 4, Ala ⁷⁹⁹to TM 10, and Arg ⁸⁸¹to TM 12.

All pRTA residues do not appear to line an ion translocation pore and are likely located in the protein/lipid bilayer complex. Considering the structural change or charge alteration for most of the missense mutations involved in pRTA, it is conceivable that these TM residing mutations would affect protein folding/helix packing in the lipid bilayer, which could lead to significant loss of mutant protein transport function. However, other than R510H, L522P, and R881C, which cause protein intracellular retention, the remaining pRTA causing mutations (S427L, T485S, G486R, and A799V) process to the plasma membrane and retain 10–50% transport function. These findings essentially rule out the possibility that the reduced transport function of the membrane-processed pRTA causing mutations is caused by dramatic protein misfolding.

Mutation of Ser ⁴²⁷to leucine induces a failure of the transporter to reverse its direction even at very negative membrane potentials. In addition, the transport is 10% of wild-type NBCe1-A. Ser ⁴²⁷has been proposed to be involved in helix interaction and leucine mutation may disrupt NBCe1-A “voltage sensing,” affect a Na ⁺coordination site, or alter the local conformation required for normal function. Ser ⁴²⁷is located in TM 1 adjacent to Ala ⁴²⁸, a residue that lines the substrate translocation pore. The bulky side chain of leucine may alter the geometry of the ion translocation pore and impair transport.

The T485S mutation is of interest because of the following considerations: (1) Serine and threonine both belong to the same amino acid category (nucleophilic) and have the same pK _a; (2) structurally, serine closely resembles threonine, but lacks a CH ₃group; (3) mutation of Thr ⁴⁸⁵to serine/cysteine impairs NBCe1-A function by 50%. These observations suggest that the CH ₃group of threonine at position 485 may have a unique role in maintaining the structure of NBCe1-A for normal ion translocation. Valine substitution restored NBCe1-A transport activity to 75% that of the wild-type, despite the fact that it is a hydrophobic amino acid. Moreover isoleucine substitution impaired transport function by 50% also highlighting the potential importance of the OH group at the 485 position. Based on these findings, it has been proposed that Thr ⁴⁸⁵may reside in a space confined position involving both CH ₃and OH chemistry that is critical for maintaining NBCe1-A in a conformation required for normal transport function. Indeed, when both CH ₃and OH groups are removed at this particular amino acid position (alanine substitution), the transport function is decreased to 30% of the wild type. This mechanism may also be applicable to the G486R mutation, which resides adjacent to Thr. ⁴⁸⁵

The L522P mutation causing pRTA is not processed to the plasma membrane in Xenopus oocytes, ECV 304, and Madin-Darby canine kidney cells, whereas an L522C mutant does not impair membrane processing. This suggests that it is the proline residue rather than the loss of leucine that causes intracellular retention of NBCe1-A. Arg ⁵¹⁰and Leu ⁵²²both reside in TM 4, a helix that carries signal anchor and stop transfer sequences, and has several residues whose mutation cause protein intracellular retention. TM 4 in NBCe1-A may act as a scaffolding helix that is important for the second stage folding of the transporter. Therefore, it is predictable that a helix disruption mutation (L522P) would significantly misfold the transporter.

The R510H and R881C mutants are also misfolded causing ER retention. Although R881C was partially expressed on the plasma membrane in the Xenopus oocytes and had significant transport activity it was fully retained intracellularly in Madin-Darby canine kidney cells and HEK cells. Arg ⁵¹⁰and Arg ⁸⁸¹are localized to TM 4 and 12, respectively, and do not reside in surface or re-entrant loops as was previously thought. Misfolding of NBCe1-A caused by these two mutations suggests that the arginine at positions 510 and 881 is involved in forming ionic interactions within the TMs to maintain the overall folding of the protein.

Potential Mutant–Specific Therapy in Proximal Renal Tubular Acidosis

In one of the nonsense mutations of NBCe1-A causing proximal RTA, a wt-CAG sequence encoding glutamine has been replaced by a UAG stop codon sequence resulting in premature truncation. Deciphering the rules dictating read-through efficiency is of primary importance for pharmacological treatment of renal tubular acidosis resulting from mutations causing premature stop codons (PSC). Aminoglycosides offer a potential therapeutic approach to treat PSC mutations by inducing ribosomal read-through. Aminoglycosides bind to the internal loop of helix 44 of the 16S ribosomal RNA, a region termed the decoding site. In both prokaryotes and eukaryotes, aminoglycosides induce miscoding by mimicking the conformation change in 16S rRNA that would be induced by a correct codon–anticodon pair, thereby compromising the integrity of codon–anticodon proofreading during translation. As a general rule, glutamine is inserted at nonsense UAG or UAA read-through sites, whereas UGA sites miscode to tryptophan.

Recent studies have shown that the NBCe1-A-Q29X mutation can be rescued in vitro by treatment with aminoglycoside antibiotics. These findings represent the first evidence that in the presence of the NBCe1-A-Q29X mutation that causes proximal renal tubular acidosis, full-length functional NBCe1-A protein can be produced. In particular these studies offer the opportunity to treat the eye phenotype locally without systemic toxicity. Recently the aminoglycoside derivative NB54 was designed which has significantly less toxicity, with stop-codon read-through potency that is significantly greater than gentamicin likely due to the presence of the flexible N-1-AHB group ( S) -2-hydroxy-4-aminobutyl group at the N-1 position). In addition non-aminoglycoside compounds such PTC124 may prove efficacious.

Additional Lessons Learned from Mice with Targeted Disruption of SLC4A4

Mice with disruption of the Slc4a4 gene (NBCe1 ^−/−mice) have a more severe (and fatal) phenotype than patients. In addition to severe hyperchloremic metabolic acidosis, they have severe volume depletion, hyponatremia, splenomegaly, intestinal obstructions, and die before weaning. In addition, NBCe1 ^−/−mice also have abnormal dentition as do patients. Paine et al. showed that enamel producing ameloblast cells express AE2a apically and NBCe1-B basolaterally. Based on this data, they hypothesized that ameloblasts mediate regulated transcellular bicarbonate secretion during the various phases of enamel formation. Results in NBCe1 ^−/−mice demonstrated that normal enamel development in mammals requires the NBCe1-B variant.

The physiologic importance of NBCe1 in mediating intestinal bicarbonate secretion is exemplified by the intestinal obstruction phenotype in NBCe1 ^−/−mice. NBCe1-B is widely expressed throughout the gastrointestinal tract. In the possum ileum, the transporter is predominantly expressed in the mid region of the villi, with lower levels of expression in the crypts, whereas in the murine colon its expression is higher in crypts than in surface cells. Although NBCn1 (SLC4A7) is also thought to function as a basolateral bicarbonate uptake mechanism in the intestine, NBCe1 is expressed at significantly higher levels than NBCn1, and in addition mice with targeted disruption of SLC4A7 don’t have an obvious intestinal phenotype.

Gain of Function

No gain of function mutations have been thus far described.

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Tags: Seldin and Giebisch's The Kidney

Jun 6, 2019 | Posted by drzezo in NEPHROLOGY | Comments Off

Abdominal Key

Fastest Abdominal Insight Engine

SLC4 Sodium-Driven Bicarbonate Transporters

Functional Categorization of the SLC4 Family

Sodium Bicarbonate Cotransporters (Electrogenic)

NBCe1 (SLC4A4 Gene)

Structural Variants

Topological and Structural Properties

Inhibitors

Familial Proximal Renal Tubular Acidosis: Molecular Mechanisms Involving NBCe1

Missense Mutations

Potential Mutant–Specific Therapy in Proximal Renal Tubular Acidosis

Additional Lessons Learned from Mice with Targeted Disruption of SLC4A4

Gain of Function

Stay updated, free articles. Join our Telegram channel

Full access? Get Clinical Tree

Abdominal Key

Fastest Abdominal Insight Engine

SLC4 Sodium-Driven Bicarbonate Transporters

Functional Categorization of the SLC4 Family

Sodium Bicarbonate Cotransporters (Electrogenic)

NBCe1 (SLC4A4 Gene)

Structural Variants

Topological and Structural Properties

Inhibitors

Familial Proximal Renal Tubular Acidosis: Molecular Mechanisms Involving NBCe1

Missense Mutations

Potential Mutant–Specific Therapy in Proximal Renal Tubular Acidosis

Additional Lessons Learned from Mice with Targeted Disruption of SLC4A4

Gain of Function

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