Disease relevance of SLC9A2

• We found that 5 polymorphisms in the 3 genes (SLC9A2, UMOD, and ELN) were associated with hypertension status, and 4 of these 5 polymorphisms were also associated with blood pressure values with a classical criterion of P<0.05 [1].
• They further demonstrate differential regulation of NHE-1 and NHE-2 mRNAs in response to acidosis and high osmolality and suggest that NHE-2 may be involved in volume regulation of IMCD cells [2].
• Intestinal ischemia resulted in increased expression of the cytoplasmic NHE regulatory factor EBP50 in NHE2 but not in NHE3 immunoprecipitates [3].
• The Na+/H+ exchanger isoforms NHE1, NHE2, and NHE3 were all found to be expressed in Ehrlich ascites tumor cells, as evaluated by Western blotting and confocal microscopy [4].
• Hypercapnia induced a approximately three-fold elevation in gill NHE2-like protein in FW animals but SW adapted fish showed inconsistent NHE3-like protein expression [5].

High impact information on SLC9A2

• Using isoform-specific primers, mRNA transcripts of the Na(+)/H(+) exchangers NHE1, NHE2, and NHE3 were detected by RT-PCR, and identities were confirmed by sequencing [6].
• The strong predominance of DRA over NHE3 and NHE2 expression in duodenum was paralleled by much higher Cl-/HCO3- than Na+/H+ exchange rates in brush border membrane vesicles and likely explains the high duodenal HCO3- secretory rates [7].
• NHE1 and NHE2 are not regulated by trafficking [8].
• Molecular cloning, sequencing, tissue distribution, and functional expression of a Na+/H+ exchanger (NHE-2) [9].
• The role of the Pro-rich regions in subcellular targeting was examined by transfection of epitope-tagged forms of NHE2 in porcine renal epithelial LLC-PK1 cells [10].

Biological context of SLC9A2

• Molecular cloning, sequencing, chromosomal localization, and tissue distribution of the human Na+/H+ exchanger (SLC9A2) [11].
• We recently reported cloning of human NHE2 (hNHE2) from a colonic cDNA library [12].
• This cDNA maps the location of the gene encoding NHE-2 to human chromosome 2q11.2 [11].
• The hNHE2 gene was mapped to chromosome 2q11 [12].
• The hNHE2 gene spans >90 kb and is organized in 12 exons intervened by 11 introns [12].

Anatomical context of SLC9A2

• The pharmacological profiles of these exchangers indicate that the human placental brush border membrane possesses the housekeeping or non-epithelial type Na(+)-H+ exchanger (NHE-1), whereas the basal membrane possesses the epithelial or apical type Na(+)-H+ exchanger (NHE-2) [13].
• Human placental syncytiotrophoblast expresses two pharmacologically distinguishable types of Na(+)-H+ exchangers, NHE-1 in the maternal-facing (brush border) membrane and NHE-2 in the fetal-facing (basal) membrane [13].
• Human NHE-2 is widely distributed in tissues of the gastrointestinal tract, kidney, heart, testes, uterus, and adrenal glands [11].
• In addition, NHE-2 mRNA was present in surface epithelial cells as well as in cells of the crypt region, suggesting the presence of NHE-2 message throughout the vertical axis of the colonic crypts [14].
• The NHE-2 message level in the distal colon was significantly higher than in the proximal colon but was evenly distributed in the small intestine [14].

Associations of SLC9A2 with chemical compounds

• In C2 cells exposed to butyrate, acetate, proprionate, or the poorly metabolized SCFA isobutyrate, apical membrane NHE3 activity and protein expression increased in a time- and concentration-dependent manner, whereas no changes were observed for NHE2 [15].
• Inhibition of NHE2 with 10(-5) M and 10(-4) M amiloride significantly increased net HCO(3)(-) output [16].
• In addition, proximal duodenal mucosal HCO(3)(-) transport was measured in humans in vivo in response to luminal perfusion of graded doses of amiloride; 10(-5)--10(-4) M amiloride was used to inhibit NHE2 and 10(-3) M amiloride to inhibit NHE3 [16].
• Thus, externally added Li+ activates NHE1 and NHE2 via a mechanism possibly involving a tyrosine kinase, causing an increase in cytoplasmic pH that could potentially affect various cell functions [17].
• RESULTS: NHE activity was inhibited significantly (approximately 50%-75%, P < .05) by .1 micromol/L 5-HT via inhibition of maximal velocity (Vmax) without any changes in apparent affinity (Km) for the substrate Na+ . NHE inhibition involved a decrease of both NHE2 and NHE3 activities [18].

Physical interactions of SLC9A2

• A PMA-induced nuclear factor that bound to the NHE2 promoter was identified as the transcription factor Egr-1 [19].

Regulatory relationships of SLC9A2

• PKC-alpha regulates basal gallbladder Na+ transport by way of stimulation of NHE isoform NHE-2 and inhibition of isoform NHE-3 [20].

Other interactions of SLC9A2

• Both NHE2 and NHE3 were localized principally to the brush border of duodenal villus cells [16].
• However, NHE2 (p < 0.001) and GAPDH (p < 0.05) mRNA expression significantly increased 18- and 3.7-fold between early first trimester and term [21].
• The expression of the isoforms NHE2 to NHE5 is restricted to specific tissues and the pattern of their expression, as well as their subcellular localization indicate that they fulfill specialized functions [22].
• The NHE2 isoform of the Na+/H+ exchanger (NHE) displays two proline-rich sequences in its C-terminal region that resemble SH3 (Src homology 3)-binding domains [10].
• 2. The activity of cysteine-sensitive alkaline phosphatase, and the abundance of villin, NHE2 and NHE3 proteins, markers of the colonic luminal membrane, were significantly enriched in the LMV compared with the original cellular homogenate [23].

Analytical, diagnostic and therapeutic context of SLC9A2

• Northern blot analysis revealed that hNHE2 message has an uneven tissue distribution, with high levels in the skeletal muscle, colon, and kidney and lower levels in the testis, prostate, ovary, and small intestine [24].
• In situ hybridization technique was used to localize NHE-2 and NHE-3 mRNA in the colon [14].
• Reverse transcriptase PCR and cDNA sequencing demonstrated that mRNA for the NHE-1 but not for NHE-2, 3, or 4 isoforms of the exchanger was expressed [25].
• Immunohistochemistry localized NHE-1 and NHE-2 to MVM and BM and NHE-3 to the MVM, BM, and cytoplasm of the syncytiotrophoblast [26].
• Western blot analysis confirmed the expression of NHE1 (91 kDa), NHE2 (90 kDa) and NHE3 (93 kDa) [27].

References