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FLASH GENE
Symbol SLC4A4 contributors: mct - updated : 20-08-2015
HGNC name solute carrier family 4, sodium bicarbonate cotransporter, member 4
HGNC id 11030
Corresponding disease
RTA2 renal tubular acidosis, proximal, with ocular abnormalities
Location 4q13.3      Physical location : 72.053.002 - 72.437.803
Synonym name
  • electrogenic Na+/HCO3- cotransporter
  • Na(+)/HCO3(-) cotransporter
  • sodium bicarbonate cotransporter 1 (sodium bicarbonate
  • cotransporter, kidney; sodium bicarbonate cotransporter,
    pancreas)
  • solute carrier family 4, sodium bicarbonate cotransporter, member 5
  • Synonym symbol(s) NBC1, SLC4A5, PNQBC, HNBC1, KNBC, NBC2, hhNMC, pNBC, NBCe1, NBC2, DKFZp781H1314, KNBC
    DNA
    TYPE functioning gene
    STRUCTURE 384.80 kb     23 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    25 - 7596 - 1094 intestinal isoform, pancreatic duct, corneal endothelium 2008 19102757
  • also called PNBC1
  • C-terminal 994 amino acids of pNBC and kNBC are identical
  • electrogenic Na+/HCO3- cotransporter variants that differ in their primary structure, transport direction, and response to secretagogues
  • regulation by secretagogues appears to be not solely dependent on its primary structure, but also on properties of the cell type in which it is expressed
  • 23 splicing 7640 - 1035 kidney (renal proximal tubule) 1999 10069984
  • also called KNBC1
  • alternative promoter in intron 3.1
  • first exon part of IV3 coupled to exon 4
  • C-terminal 994 amino acids of pNBC and kNBC are identical
  • also electrogenic
  • 26 splicing 7693 - 1079 strong expression in pancreas and expression in heart and brain 1999 10069984
  • also called HNBC1
  • identical to KNBC1, except for the N-terminus, where the first 85 amino acids in HNBC1 replace the first 41 amino acids of KNBC1
  • last 43 nt of IV1 coupled to exon 2
  • electrogenic Na+-HCO-3 cotransporter
  • EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon   Homo sapiens
     pancreas exocrine     Homo sapiens
     pharynx     Homo sapiens
     salivary glandparotid  highly Homo sapiens
    Endocrinepancreas     Homo sapiens
    Nervousbrain     Mus musculus
     plexus choroid     Rattus norvegicus
    Urinarykidneytubuleconvoluted tubuleproximal tubulehighly
     kidneynephron   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveameloblast Homo sapiens
    Nervousastrocyte Mus musculus
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal cytosolic domain involved in protein interactions
  • 14 TMs in its transmembrane region
  • 5 transmembrane segments with greater average size compared with SLC4A1
  • hydrophilic intracellular N-terminal regions including binding sites for hemoglobin EPB41 and other proteins
  • a C cytoplasmic terminal forming the exchange channel, with a dihydrophobic FL motif (residues 1013-1014)
  • C-terminal transmembrane region is tightly folded with unique structural and functional features that differ from SLC4A1
  • secondary structure precise location of the FL motif in the primary sequence of SLC4A4 are strict requirements for the alpha-helical structure of the C-terminal cytoplasmic domain and for targeting of SLC4A4 to the basolateral membrane
    HOMOLOGY
    Homologene
    FAMILY
  • solute carrier family 4, sodium bicarbonate
  • anion exchanger family
  • xanthine/uracyl permease family
  • CATEGORY transport carrier
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
    text basolateral membrane
    basic FUNCTION
  • involved in the transport of sodium and bicarbonate out of the corneal stroma and into the aqueous humor
  • mediating bicarbonate absorption from renal proximal tubules
  • electrogenic and plays an important role in bicarbonate reabsorption in kidney proximal tubule
  • SLC2A4, SLC4A4 play important roles in amelogenesis
  • playing a major role in renal bicarbonate absorption via proximal tubules and therefore is crucial for maintaining normal blood pH
  • transports sodium and bicarbonate across the basolateral membrane of the renal proximal tubule
  • its expression is required for the development of normal enamel
  • is electrogenic because it has an apparent Na+:HCO&
  • 8323;&
    8315; stoichiometry of 1:2 or 1:3
  • is a key element in a feedforward mechanism linking excitatory synaptic transmission to fast modulation of glycolysis in astrocytes
  • regulation of anion fluxes in insulin-producing cells may involve both SLC4A4 and ANO1
  • encodes electrogenic, amiloride-insensitive Na-HCO3 cotransport in proximal colon
  • is a high-affinity bicarbonate carrier in cortical astrocytes
  • SLC4A4 and the trafficking regulator gene COPA, plays an important role in early endosome maturation
  • COPA and SLC4A4 are required for cellular entry of arginine-rich peptides
  • major regulator of intracellular, and extracellular pH
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling sensory transduction/vision
    a component
  • interaction with CA2/CA4 at the inner surface of the plasma membrane, indicating that SLC4A4/CAII interaction is needed for full pH(i) recovery activity
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • target molecule of AHCYL1 (AHCYL1 may also be responsible for the characteristic difference in physiological roles of SLC4A4 variants)
  • target molecule of AHCYL1 and AHCYL1 has an important role in pH regulation through SLC4A4
  • AHCYL1 may be a cytosolic factor that modulates the apparent affinity for Mg2+ intracellular in inhibition of SLC4A in mammalian cells
  • site-specific interactions of HSPA13 with SLC4A4 and SLC9A1 and subsequent modulation of membrane transporter expression
  • AHCYL2 is a potential regulator of SLC4A4 in mammalian cells
  • cell & other
    REGULATION
    activated by directly stimulated by carbonic anhydrase (CA) II
    ASSOCIATED DISORDERS
    corresponding disease(s) RTA2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    associated with unfavorable prognosis in Colorectal cancer
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • CEACAM7, SLC4A4, GCG and CLCA1 may be prognostic markers or therapeutic targets of Colorectal cancer
  • biomarker for thyroid cancer exhibiting differences in the correlation coefficients between benign and malignant samples that indicate its discriminatory power
  • Therapy target
    ANIMAL & CELL MODELS
  • (NBCe1&
  • 8722;/&
    8722; mice) have a severe phenotype, severe metabolic acidosis, growth retardation, reduced plasma Na+, hyperaldosteronism, splenomegaly, intestinal obstructions, and die before weaning , and also are described as having an abnormal dentition with “chalk-white” and “brittle” enamel
  • mice lacking NBCe1 have enamel abnormalities