Disease relevance of SLC9A5

• Given the allelic association, further evaluation of the role of NHE5 in ESRD susceptibility appears warranted [1].
• Mutation analysis of the sodium/hydrogen exchanger gene (NHE5) in familial paroxysmal kinesigenic dyskinesia [2].

High impact information on SLC9A5

• The neuronal Na(+)/H(+) exchanger NHE5 isoform not only resides in the plasma membrane but also accumulates in recycling vesicles by means of clathrin-mediated endocytosis [3].
• To further investigate the underlying molecular mechanisms, a human brain cDNA library was screened for proteins that interact with the cytoplasmic C-terminal region of NHE5 by using yeast two-hybrid methodology [3].
• Full-length NHE5 and beta-arrestin2 also associated in intact cells, as revealed by their coimmunoprecipitation from extracts of transfected CHO cells [3].
• By contrast, disruption of the F-actin cytoskeleton with cytochalasin D increased cell surface NHE5 activity and abundance [4].
• Similarly, in nerve growth factor-differentiated neuroendocrine PC12 cells and primary hippocampal neurons, immunolabeling of NHE5 was detected in endomembrane vesicles in the perinuclear region of the cell body but also along the processes [4].

Biological context of SLC9A5

• Molecular cloning and physical and genetic mapping of a novel human Na+/H+ exchanger (NHE5/SLC9A5) to chromosome 16q22.1 [5].
• 1. A polymorphic dinucleotide (GT/CA)n repeat contained in the NHE5 cosmid was identified and developed into a microsatellite PCR marker [5].
• Fluorescence in situ hybridization analysis of a cosmid containing NHE5 to human metaphase chromosomes localized the NHE5 gene to the cytogenetic interval 16q21-q22 [5].
• Polymerase chain reaction amplification of brain cDNA yielded products in which each of the introns had been correctly excised, whereas the introns were retained in products from spleen and testis, suggesting that the NHE5 transcripts expressed in these organs do not encode a functional transporter [6].
• We report here the cloning, primary structure, heterologous expression, tissue distribution, and localization of a cDNA encoding rat NHE5, a fifth member of the mammalian plasma membrane Na+/H+ exchanger (NHE) gene family [7].

Anatomical context of SLC9A5

• Northern blot analysis demonstrated that the NHE5 gene is expressed in brain, testis, spleen, and skeletal muscle [5].
• A panel of somatic cell hybrids containing various portions of chromosome 16 was used to refine further the placement of NHE5 within band 16q22 [5].
• Northern blot analysis demonstrated that the mRNA encoding NHE5 is expressed in multiple regions of the brain, including hippocampus, consistent with the possibility that it regulates intracellular pH in hippocampal and other neurons [6].
• In situ hybridization of rat brain sections revealed significant NHE5 mRNA levels in the dentate gyrus with lower levels observed in the hippocampus and cerebral cortex [7].
• More detailed characterization in AP-1 cells using organelle-specific markers showed that NHE5 co-localized with internalized transferrin, a marker of recycling endosomes [4].

Associations of SLC9A5 with chemical compounds

• We propose that RACK1 activates NHE5 both by integrin-dependent and independent pathways, which may coordinate cellular ion homeostasis during cell-matrix adhesion [8].

Regulatory relationships of SLC9A5

• Together, these results suggest that SCAMP2 regulates NHE5 transit through recycling endosomes and promotes its surface targeting in an Arf6-dependent manner [9].

Other interactions of SLC9A5

• The intron/exon organization of the NHE5 gene was analyzed and found to be very similar to that of the NHE3 gene [6].
• To date, 5 isoforms of NHE have been cloned in mammals (NHE1 to NHE5) [1].
• 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 [10].
• The segmental location and function of NHE-5 and NHE-6 in the kidney are unknown at present [11].

Analytical, diagnostic and therapeutic context of SLC9A5

• RT-PCR analysis of rat kidney RNA using primers specific for NHE isoforms -2, -3, -4 and rat brain RNA using primer specific for NHE-5 isoform yielded products of expected size, whereas WBC depleted RNA under identical conditions yielded no products [12].

References