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FLASH GENE

Symbol

SLC9A3

contributors: mct/pgu - updated : 11-10-2018

HGNC name	solute carrier family 9 (sodium/hydrogen exchanger), isoform 3
HGNC id	11073

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	DIAR8 diarrhea 8, secretory sodium, congenital
Location	5p15.33      Physical location : 473.333 - 524.549
Synonym symbol(s)	APNH3, NHE3, SLC9A3B, MGC126718, MGC126720

DNA

TYPE	functioning gene
STRUCTURE	52.45 kb     17 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Binding site   transcription factor
text structure	Sp1 and Sp3 acting as positive regulators of the SLC9A3 expression

MAPPING

cloned

Y

linked

Y

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004174 17 - 2777 NP_004165 - 834 - 2015 26377793 NM_001284351 17 - 3983 NP_001271280 - 825 - 2015 26377793

EXPRESSION

Type	restricted

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       predominantly Homo sapiens Reproductive male system male genital tract epididymis     Homo sapiens   male system male genital tract vas deferens     Homo sapiens Respiratory respiratory tract trachea       Urinary kidney tubule convoluted tubule proximal tubule   Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular

cells

System Cell Pubmed Species Stage Rna symbol Digestive epithelial cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

perinatal, growth/childhood

Text	maturational increase in postnatal brush-border membrane (BBM) vesicle SLC9A3 protein abundance and decrease in SLC9A8 protein abundance

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	ten (? twelve) transmembrane segments protein
	a large acidic cytoplasmic C terminal domain

HOMOLOGY

Homologene

FAMILY

solute carrier protein family 9,sodium/hydrogen exchange

CATEGORY

transport carrier

SUBCELLULAR LOCALIZATION	plasma membrane
text	expressed on the apical membrane of intestinal epithelial cells

basic FUNCTION	involved in intracellular pH regulation and cell volume
	playing an essential role for Na+ absorption in the ileum and is expressed in a cell-specific manner in the apical membrane of the intestinal epithelial cells
	having a role in the maintenance of acid-base balance
	plays an important role in neutral Na(+) transport in mammalian epithelial cells
	modulatory effect of the SLC9A3 gene on susceptibility to infections and pulmonary function in children with cystic fibrosis
	role of SLC9A3 in the acidification of the male reproductive tract and its requirement for male fertility
	is responsible for the bulk of salt reabsorption in the proximal tubule, and its activity may be affected the most by the increase in length of this renal segment
	plays an important role in fluid and bicarbonate reabsorption in the proximal convoluted tubule but does not play an important role in NH4 excretion
	partially associate with lipid rafts in the native brush border membrane (BBM), and SLC9A3 raft association had an impact on SLC9A3 transport activity and regulation
	is located in chemosensitive areas of the medulla oblongata and plays an important role in the central control of respiration
	can act as a direction sensor for cells and SLC9A3 phosphorylation in persistent directional cell migration does not involve PI3K/AKT1 during electrotaxis
	located in the apical dense microvilli (brush border), and plays a major role in the reabsorption of NaCl and water in the renal proximal tubule
	may play a role in the pathogenesis of cholesterol gallstone disease (CGD)
	is a major route of sodium absorption in the intestine and kidney 0)
	renal SLC9A3 is required to maintain blood pressure and steady-state plasma sodium levels when dietary sodium chloride intake is modified
	Na&
	8314;/H&
	8314; exchanger, regulating the transepithelial absorption of Na&
	8314; and water
	has a vital role in acrosomal formation during spermiogenesis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

SLC9A3, SHANK2, and ARHGEF7 form a macromolecular complex when expressed heterologously in mammalian cells

INTERACTION

DNA

RNA

small molecule

protein	interacting with SHANK2 (novel interacting protein that is involved in the fine regulation of transepithelial salt and water transport through affecting SLC9A3 expression and activity)
	interacting with PDZK1 (reconstitutes calcium inhibition of SLC9A3 activity by anchoring SLC9A3 basally and releasing it with elevated Ca(2+))
	SYT1 plays an important role in cAMP-stimulated endocytosis of apical SLC9A3 through cAMP-dependent phosphorylation of S605 that is required for NHE3 and SYT1 association
	AHCYL1 is critically involved in mediating activation of SLC9A3 by AGT via a Ca(2+)/calmodulin-dependent protein kinases II-dependent pathway
	SGK2 may play a previously unrecognized role in the control of transtubular Na(+) transport through SLC9A3 in the proximal tubule
	cAMP-dependent inhibition of SLC9A3 activity requires either SLC9A3R1 or SLC9A3R2
	role for SLC9A1 in the long-term regulation of renal tubule function, suggesting that the regulatory interaction whereby SLC9A1 enhances the activity of SLC9A3 in the medullary thick ascending limb and plays a role in the chronic regulation of HCO(3)(-) absorption
	SGK3 is a novel endosomal kinase that acutely regulates SLC9A3 in a PI3K-dependent mechanism
	AHCYL1 plays an important role in pHi regulation, mediated by SLC9A3, and further regulated by STK39
	MYO6 is required for basal and stimulated endocytosis of SLC9A3 in intestinal cells, suggesting that MYO6 also moves SLC9A3 down the microvillus
	role for PER1 in the transcriptional regulation of SLC9A3 and SLC5A1 in the kidney
	SLC9A3 interacts with CFTR in the pancreatic duct and functions as a genetic modifier of CF
	interdependence between SLC9A3 and CFTR is critical for maintaining a precise microenvironment in the epithelial cytoarchitecture of the male reproductive tract
	direct interaction of MLXIPL with the SLC2A5 promoter, but not the SLC9A3 promoter, in the small intestine

cell & other

REGULATION

Phosphorylated by

RPS6KA3 (RPS6KA3 is a new kinase that regulates SLC9A3 activity by direct phosphorylation)

Other	transcriptional regulation by serotonin in intestinal epithelial cells
	regulated by glucocorticoids (have been found to regulate SLC9A3 function in the intestine)
	regulated by thyroid hormone (plays a potential role in the developmental isoform change from SLC9A8 to SLC9A3 and decreases SLC9A8 activity

ASSOCIATED DISORDERS

corresponding disease(s)

DIAR8

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in Barrett esophagus tumoral   amplification     in early stages of non-small cell lung cancer constitutional     --low   in patients with ulcerative colitis

Susceptibility

to the sudden infant death syndrome (SIDS) to preeclampsia

Variant & Polymorphism other	the level of SLC9A3 expression in brainstem tissue may contribute to the vulnerability of infants for SIDS
	Rs4957061 in SLC9A3 was significantly associated with a reduced risk of preeclampsia in whites

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	depleted Slc9a3 in male mice causes infertility due to the abnormal dilated lumen of the rete testis and efferent ductules
	Cftr expression was dramatically decreased in the epididymis and vas deferens of Slc9a3 knockout mice