Mineralocorticoid receptor blockade improves arginine transport and nitric oxide generation through modulation of cationic amino acid transporter-1 in endothelial cells

Shashar, Moshe; Hod, Tamar; Chernichovski, Tamara; Angel, Avital; Kazan, Shaul; Grupper, Ayelet; Naveh, Sivan; Bassat, Orit Kliuk‐Ben; Weinstein, Talia; Schwartz, Idit F.

doi:10.1016/j.niox.2018.07.007

Cited by 3 publications

(2 citation statements)

References 29 publications

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“…In AA/Na + symporters of SLC7A (CATs), SLC1A and SLC38A families, the third extracellular peptide loop is also within ∼10Å of the membrane and has 1 to 3 conserved N-glycosylation sites where galectin cross-linking is possible. Indeed, N-glycosylation of sites in SLC7A1, SLC7A3 and SLC1A5 promotes stability and activity at the cell surface by interacting with galectins, (75,115,116). The AA/Na + symporters have the potential to cluster with SLC3A2*SLC7A5 and regulate diffusion-limited exchange as suggested by the synchronized flux of BCAA and Glu when BSA was the only source of AAs (Fig.…”

Section: Discussionmentioning

confidence: 99%

SLC3A2 N-glycosylation and alternate evolutionary trajectories for amino acid metabolism

Zhang

Shafaq-Zadah

Pawling

et al. 2022

Preprint

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SLC3A2 (4F2hc, CD98) is an adaptor to the SLC7A exchangers and has undergone extensive repositioning of N-glycosylation sites with vertebrate evolution, presumably in synchrony with the species-specific demands of metabolism. The SLC3A2*SLC7A5 heterodimer imports essential amino acids (AA) and thereby stimulates mTOR signaling, while SLC3A2*SLC7A11 imports cystine required for glutathione synthesis and mitigation of oxidative stress. Analysis of SLC3A2 N-glycans revealed stable site-specific profiles of Golgi remodeling, apart from the conserved N365 site where branching and poly-N-acetylglucosamine content were sensitive to the insertion of lost ancestral sites and to metabolism. N-glycans at N381 and N365 stabilized SLC3A2 in the galectin lattice and opposed endocytosis, while N365 which is nearest the membrane, also promoted down-regulation by galectin-driven clathrin-independent endocytosis (glycolipid-lectin GL-Lect). This is the first report of both positive and negative regulation by galectin binding to N-glycans that are strategically positioned in the same membrane glycoproteins. Proteomics analysis in SLC3A2 mutant HeLa cells with induced re-expression of SLC3A2 as bait revealed the canonical non-N-glycosylated interactors, SLC7A5 and SLC7A11 exchangers, but also AA transporters that were dependent on SLC3A2 N-glycosylation, and are themselves, N-glycosylated AA/Na+ symporters (SLC7A1, SLC38A1, SLC38A2, SLC1A4, SLC1A5). The results suggest that the N-glycans on SLC3A2 regulate clustering of SLC7A exchangers with AA/Na+ symporters, thereby promoting Gln/Glu export-driven import of essential AA and cystine, with the potential to adversely impact redox balance. The evolution of modern birds (Neoaves) led to improved control of bioenergetics with the loss of genes including SLC3A2, SLC7A-5, -7, -8, -10, BCAT2, KEAP1, as well as duplications of SLC7A9, SLC7A11 and the Golgi branching enzymes MGAT4B and MGAT4C known to enhance affinities for galectins. Analyzing the fate of these and other genes in the down-sized genomes of birds, spanning ~10,000 species and >100 Myr of evolution, may reveal the mystery of their longevity with prolonged vitality.

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Section: Discussionmentioning

confidence: 99%

SLC3A2 N-glycosylation and alternate evolutionary trajectories for amino acid metabolism

Zhang

Shafaq-Zadah

Pawling

et al. 2022

Preprint

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“…Polyamines, including putrescine (PUT), spermidine (SPD), and spermine (SPM), are synthesized by utilizing glutamine, arginine, and proline as substrates, and methionine is also used for spermine synthesis, which is essential for cell proliferation, inflammation control, transmembrane transport, and tissue repair. 18 , 19 Previously, Adhami hypothesized that polyamines convert DNA to an immunogenic structure to stabilize autoantigens. 20 However, it is not clear whether polyamines alter the differentiation of Th subsets.…”

Section: Introductionmentioning

confidence: 99%