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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon     Homo sapiens   pancreas exocrine         Homo sapiens   pharynx         Homo sapiens   salivary gland parotid     highly Homo sapiens Endocrine pancreas         Homo sapiens Nervous brain         Mus musculus   plexus choroid         Rattus norvegicus Urinary kidney tubule convoluted tubule proximal tubule highly   kidney nephron

cells

System Cell Pubmed Species Stage Rna symbol Digestive ameloblast Homo sapiens Nervous astrocyte 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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