scholarly journals Amino acid transporter B0AT1 influence on ADAM17 interactions with SARS-CoV-2 receptor ACE2 putatively expressed in intestine, kidney, and cardiomyocytes

2020 ◽  
Author(s):  
Jacob T. Andring ◽  
Robert McKenna ◽  
Bruce R. Stevens
Keyword(s):  
Amino Acid ◽  
Plasma Membranes ◽  
Renin Angiotensin System ◽  
Neck Region ◽  
Cell Types ◽  
Amino Acid Transporter ◽  
Common Denominator ◽  
Organ Systems ◽  
Acid Transporter

ABSTRACTSARS-CoV-2 exhibits significant experimental and clinical gastrointestinal, renal, and cardiac muscle tropisms responsible for local tissue-specific and systemic pathophysiology capriciously occurring in about half of COVID-19 patients. The underlying COVID-19 mechanisms engaged by these extra-pulmonary organ systems are largely unknown. We approached this knowledge gap by recognizing that neutral amino acid transporter B0AT1 (alternately called NBB, B, B0 in the literature) is a common denominator expressed nearly exclusively by three particular cell types: intestinal epithelia, renal proximal tubule epithelium, and cardiomyocytes. B0AT1 provides uptake of glutamine and tryptophan. The gut is the main depot expressing over 90% of the body’s entire pool of SARS-CoV-2 receptor angiotensin converting enzyme-2 (ACE2) and B0AT1. Recent cryo-EM studies established that ACE2 forms a thermodynamically favored dimer-of-heterodimers complex with B0AT1 assembled in the form of a dimer of two ACE2:B0AT1 heterodimers anchored in plasma membranes. Prior epithelial cell studies demonstrated ACE2 chaperone trafficking of B0AT1. This contrasts with monomeric expression of ACE2 in lung pneumocytes, in which B0AT1 is undetectable. The cell types in question also express a disintegrin and metalloproteinase-17 (ADAM17) known to cleave and shed the ectodomain of monomeric ACE2 from the cell surface, thereby relinquishing protection against unchecked renin-angiotensin-system (RAS) events of COVID-19. The present study employed molecular docking modeling to examine the interplaying assemblage of ACE2, ADAM17 and B0AT1. We report that in the monomer form of ACE2, neck region residues R652-N718 provide unimpeded access to ADAM17 active site pocket, but notably R708 and S709 remained >10-15 Å distant. In contrast, interference of ADAM17 docking to ACE2 in a dimer-of-heterodimers arrangement was directly correlated with the presence of a neighboring B0AT1 subunit complexed to the partnering ACE2 subunit of the 2ACE2:2B0AT1] dimer of heterodimers, representing the expression pattern putatively exclusive to intestinal, renal and cardiomyocyte cell types. The monomer and dimer-of-heterodimers docking models were not influenced by the presence of SARS-CoV-2 receptor binding domain (RBD) complexed to ACE2. The results collectively provide the underpinnings for understanding the role of B0AT1 involvement in COVID-19 and the role of ADAM17 steering ACE2 events in intestinal and renal epithelial cells and cardiomyocytes, with implications useful for consideration in pandemic public hygiene policy and drug development.

scholarly journals Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo

2021 ◽  
Vol 22 (4) ◽  
pp. 1707
Author(s):  
Sebastian Granitzer ◽  
Raimund Widhalm ◽  
Martin Forsthuber ◽  
Isabella Ellinger ◽  
Gernot Desoye ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amino Acid ◽  
De Novo ◽  
Structural Similarity ◽  
Amino Acid Transporter ◽  
Cell Number ◽  
Mehg Exposure ◽  
Acid Transporter ◽  
And Oxidative Stress

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.

Circular RNA NF1-419 Inhibits Proliferation and Induces Apoptosis by Regulating Lipid Metabolism in Astroglioma Cells

2021 ◽  
Vol 16 ◽  
Author(s):  
Ran Li ◽  
Xiaocui Tang ◽  
Changqiong Xu ◽  
Yinrui Guo ◽  
Longkai Qi ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Amino Acid ◽  
Tumor Growth ◽  
Ganoderma Lucidum ◽  
Amino Acid Transporter ◽  
Cationic Amino Acid Transporter ◽  
Cationic Amino Acid ◽  
Acid Transporter ◽  
Astroglioma Cells

Background: Astroglioma is the most common primary tumor of the central nervous system. Currently, there is no effective treatment for astroglioma. In the present study, the extract (L3) from Ganoderma Lucidum (G.lucidum) was found to inhibit the growth of astroglioma U87 cells and change the expression of circular RNAs (circRNAs). One of these, including the circular NF1-419 (circNF1-419), was of interest because NF1 gene is a classic tumor suppressor gene. Objective: The functional role of circ-NF1-419 in the inhibition of astroglioma cells remains unknown. This study focuses on the role of circNF1-419 in functional abnormalities of U87 astroglioma cells and aims to elaborate on its regulatory mechanism. Methods: The circNF1-419 overexpressing U87 (U87-NF1-419) cells were constructed. We generated U87-NF1-419 to evaluate the role of circNF1-419 on cell cycle, apoptosis, proliferation, tumor growth and metabolic regulation. Finally, we used docking screening to identify compounds in G. lucidum extracts that target circ-419. Results: U87-NF1-419 can promote cell apoptosis and regulate lipid metabolism through glycerophospholipid metabolism and retrograde endocannabinoid signaling. Further examinations revealed that the expression of metabolic regulators, such as L-type voltage-operated calcium channels (L-VOCC), phospholipase C-β3 (PLCβ3), Mucin1, cationic amino acid transporter 4 (CAT4), cationic amino acid transporter 1 (CAT1) and a kinase (PRKA) anchor protein 4 (AKAP4) was inhibited, while phosphatidylserine synthase 1 (PTDSS1) was enhanced in U87-NF1-419 cells. In vivo experiments showed that circNF1-419 inhibits tumor growth in BALB/C nude mice, and enhanced AKAP4 and PTDSS1 in tumor tissues. The virtual docking screening results supported that ganosporeric acid A, ganodermatriol, ganoderic acid B and α-D-Arabinofuranosyladenine in L3 could activate circNF1-419 in astroglioma treatment. Conclusion: This study indicated that circNF1-419 could be a therapeutic target for the clinical treatment of astroglioma. L3 from Ganoderma Lucidum (G.lucidum) could inhibit astroglioma growth by activating circNF1-419.

Regulatory pathways and uptake ofl-DOPA by capillary cerebral endothelial cells, astrocytes, and neuronal cells

2001 ◽  
Vol 280 (2) ◽  
pp. C333-C342 ◽  
Author(s):  
B. Sampaio-Maia ◽  
M. P. Serrão ◽  
P. Soares-da-Silva
Keyword(s):  
Amino Acid ◽  
Neuroblastoma Cells ◽  
Cell Types ◽  
Amino Acid Transporter ◽  
Nitric Oxide Donor ◽  
Intracellular Camp ◽  
Regulatory Pathways ◽  
Dopa Accumulation ◽  
Acid Transporter ◽  
Dopa Uptake

We examined the nature and regulation of the inwardl-3,4-dihydroxyphenylalanine (l-DOPA) transporter in rat capillary cerebral endothelial (RBE4) cells, type 1 astrocytes (DI TNC1), and Neuro-2a neuroblastoma cells. In all three cell types, the inward transfer of l-DOPA was largely promoted through the 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid-sensitive and sodium-independent L-type amino acid transporter. Only in DI TNC1 cells was the effect of maneuvers that increase intracellular cAMP levels accompanied by increases inl-DOPA uptake. Also, only in DI TNC1 cells was the effect of the guanylyl cyclase inhibitor LY-83583 accompanied by a 65% increase in l-DOPA accumulation, whereas the nitric oxide donor sodium nitroprusside produced a 25% decrease inl-DOPA accumulation. In all three cell types, the Ca2+/calmodulin inhibitors calmidazolium and trifluoperazine inhibited l-DOPA uptake in a noncompetitive manner. Thapsigargin (1 and 3 μM) and A-23187 (1 and 3 μM) failed to alter l-DOPA accumulation in RBE4 and Neuro-2a cells but markedly increased l-DOPA uptake in DI TNC1cells. We concluded that l-DOPA in RBE4, DI TNC1, and Neuro-2a cells is transported through the L-type amino acid transporter and appears to be under the control of Ca2+/calmodulin-mediated pathways. Astrocytes, however, are endowed with other processes that appear to regulate the accumulation of l-DOPA, responding positively to increases in intracellular Ca2+ and cAMP and to decreases in cGMP.

scholarly journals Amino Acid Transport Defects in Human Inherited Metabolic Disorders

2019 ◽  
Vol 21 (1) ◽  
pp. 119 ◽  
Author(s):  
Raquel Yahyaoui ◽  
Javier Pérez-Frías
Keyword(s):  
Amino Acid ◽  
Metabolic Disorders ◽  
Strong Association ◽  
Cell Types ◽  
Amino Acid Transporter ◽  
Molecular Defect ◽  
Amino Acid Transporters ◽  
Inherited Disorders ◽  
Laboratory Findings ◽  
Acid Transporter

Amino acid transporters play very important roles in nutrient uptake, neurotransmitter recycling, protein synthesis, gene expression, cell redox balance, cell signaling, and regulation of cell volume. With regard to transporters that are closely connected to metabolism, amino acid transporter-associated diseases are linked to metabolic disorders, particularly when they involve different organs, cell types, or cell compartments. To date, 65 different human solute carrier (SLC) families and more than 400 transporter genes have been identified, including 11 that are known to include amino acid transporters. This review intends to summarize and update all the conditions in which a strong association has been found between an amino acid transporter and an inherited metabolic disorder. Many of these inherited disorders have been identified in recent years. In this work, the physiological functions of amino acid transporters will be described by the inherited diseases that arise from transporter impairment. The pathogenesis, clinical phenotype, laboratory findings, diagnosis, genetics, and treatment of these disorders are also briefly described. Appropriate clinical and diagnostic characterization of the underlying molecular defect may give patients the opportunity to avail themselves of appropriate therapeutic options in the future.

Role of l-Type Amino Acid Transporter 1 at the Inner Blood-Retinal Barrier in the Blood-to-Retina Transport of Gabapentin

2018 ◽  
Vol 15 (6) ◽  
pp. 2327-2337 ◽  
Author(s):  
Shin-ichi Akanuma ◽  
Atsuko Yamakoshi ◽  
Takeshi Sugouchi ◽  
Yoshiyuki Kubo ◽  
Anika M. S. Hartz ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Transporter ◽  
Blood Retinal Barrier ◽  
Acid Transporter

Sex-dependent activity of the spinal excitatory amino acid transporter: Role of estrous cycle

Neuroscience ◽  
2016 ◽  
Vol 333 ◽  
pp. 311-319 ◽  
Author(s):  
Jahangir Sajjad ◽  
Valeria D. Felice ◽  
Anna V. Golubeva ◽  
John F. Cryan ◽  
Siobhain M. O’Mahony
Keyword(s):  
Amino Acid ◽  
Estrous Cycle ◽  
Excitatory Amino Acid ◽  
Amino Acid Transporter ◽  
Excitatory Amino Acid Transporter ◽  
Dependent Activity ◽  
Acid Transporter

scholarly journals A Putative Amino Acid Transporter Is Specifically Expressed in Haustoria of the Rust Fungus Uromyces fabae

1997 ◽  
Vol 10 (4) ◽  
pp. 438-445 ◽  
Author(s):  
Matthias Hahn ◽  
Ulrike Neef ◽  
Christine Struck ◽  
Michael Göttfert ◽  
Kurt Mendgen
Keyword(s):  
Amino Acid ◽  
Plasma Membranes ◽  
Rust Fungus ◽  
Amino Acid Transporter ◽  
Infected Leaf ◽  
Molecular Evidence ◽  
Special Role ◽  
Coding Region ◽  
Uromyces Fabae ◽  
Acid Transporter

A cDNA library constructed from haustoria of the rust fungus Uromyces fabae was screened for clones that are differentially expressed in haustoria. One family of cDNAs (in planta-induced gene 2 [PIG2]) was isolated and found to encode a protein with high homologies to fungal amino acid transporters. A cDNA clone containing the complete coding region of PIG2 and the corresponding genomic clone were isolated and sequenced, revealing the presence of 17 introns in the PIG2 gene. Expression of PIG2 mRNA appeared to be restricted to haustoria. With antibodies raised against synthetic peptides, the PIG2-encoded protein was found in membrane fractions of isolated haustoria but not of germinated rust spores. With immunofluo-rescence microscopy, the putative amino acid transporter was localized to plasma membranes of the haustorial bodies, but not detected in the haustorial neck, haustorial mother cells, or intercellular fungal hyphae growing within infected leaf tissue. These data present for the first time molecular evidence that the rust haustorium plays a special role in the uptake of nutrients from an infected host cell.

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