Selective tonicity-induced expression of the neutral amino-acid transporter SNAT2 in oligodendrocytes in rat brain following systemic hypertonicity

Maallem, Saïd; Mutin, M; González‐González, Inmaculada M.; Zafra, Francisco; Tappaz, Marcel

doi:10.1016/j.neuroscience.2008.01.047

Cited by 19 publications

(14 citation statements)

References 52 publications

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“…Slc38a2 is a sodium-coupled transporter of neutral amino acids that has been previously reported as differentially expressed or activated in response to hyperosmolarity. 40,41 As expected, the ion-transporting genes were upregulated by elevated osmolarity. One solute-carrier gene, Slco4a1, was found consistently upregulated with a 6.6-fold change at 4 h after stress.…”

Section: Transcriptional Changes Upon Application Of Hyperosmotic Stresssupporting

confidence: 66%

Transcriptomic responses to sodium chloride‐induced osmotic stress: A study of industrial fed‐batch CHO cell cultures

Shen

Kiehl

Khattak

et al. 2010

Biotechnology Progress

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The rapidly expanding market for monoclonal antibody and Fc-fusion-protein therapeutics has increased interest in improving the productivity of mammalian cell lines, both to alleviate capacity limitations and control the cost of goods. In this study, we evaluated the responses of an industrial CHO cell line producing an Fc-fusion-protein to hyperosmotic stress, a well-known productivity enhancer, and compared them with our previous studies of murine hybridomas (Shen and Sharfstein, Biotechnol Bioeng. 2006;93:132-145). In batch culture studies, cells showed substantially increased specific productivity in response to increased osmolarity as well as significant metabolic changes. However, the final titer showed no substantial increase due to the decrease in viable cell density. In fed batch cultures, hyperosmolarity slightly repressed the cellular growth rate, but no significant change in productivity or final titer was detected. To understand the transcriptional responses to increased osmolarity and relate changes in gene expression to increased productivity and repressed growth, proprietary CHO microarrays were used to monitor the transcription profile changes in response to osmotic stress. A set of osmotically regulated genes was generated and classified by extracting their annotations and functionalities from online databases. The gene list was compared with results previously obtained from similar studies of murine-hybridoma cells. The overall transcriptomic responses of the two cell lines were rather different, although many functional groups were commonly perturbed between them. Building on this study, we anticipate that further analysis will establish connections between productivity and the expression of specific gene(s), thus allowing rational engineering of mammalian cells for higher recombinant-protein productivity.

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Section: Transcriptional Changes Upon Application Of Hyperosmotic Stresssupporting

confidence: 66%

Transcriptomic responses to sodium chloride‐induced osmotic stress: A study of industrial fed‐batch CHO cell cultures

Shen

Kiehl

Khattak

et al. 2010

Biotechnology Progress

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“…However, when cell proliferation is required, a rapid growth can be achieved when connexins form gap junctions. A cooperative behavior among hypertonic-stressed cells can also take place outside the kidney like in the brain (37) or the cornea (35) when their tissues experience osmotic variations.…”

Section: Discussionmentioning

confidence: 99%

Gap junctions favor normal rat kidney epithelial cell adaptation to chronic hypertonicity

Desforges

Savarin

Bounedjah

et al. 2011

American Journal of Physiology-Cell Physiology

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Upon hypertonic stress most often resulting from high salinity, cells need to balance their osmotic pressure by accumulating neutral osmolytes called compatible osmolytes like betaine, myo-inositol, and taurine. However, the massive uptake of compatible osmolytes is a slow process compared with other defense mechanisms related to oxidative or heat stress. This is especially critical for cycling cells as they have to double their volume while keeping a hospitable intracellular environment for the molecular machineries. Here we propose that clustered cells can accelerate the supply of compatible osmolytes to cycling cells via the transit, mediated by gap junctions, of compatible osmolytes from arrested to cycling cells. Both experimental results in epithelial normal rat kidney cells and theoretical estimations show that gap junctions indeed play a key role in cell adaptation to chronic hypertonicity. These results can provide basis for a better understanding of the functions of gap junctions in osmoregulation not only for the kidney but also for many other epithelia. In addition to this, we suggest that cancer cells that do not communicate via gap junctions poorly cope with hypertonic environments thus explaining the rare occurrence of cancer coming from the kidney medulla.

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“…The presence of SNAT1 and/or SNAT2 protein on brain cells other than neurons, such as in leptomeninges, ependymal cells, and choroid plexus (6,8), in astrocytes and oligodendrocytes (8,81) as well as both excitatory and inhibitory neurons suggests roles outside of neurotransmitter glutamate regeneration. Interestingly, recent evidence strongly supports a role for SNAT1 in the brain to supply neutral amino acids for local protein synthesis related to synaptic remodeling and plasticity in pyramidal neuronal dendrites (82).…”

Section: Adaptive Regulation Of Snat2 Mrna Expression By Amino Acid Dmentioning

confidence: 99%

SNAT2 Amino Acid Transporter Is Regulated by Amino Acids of the SLC6 γ-Aminobutyric Acid Transporter Subfamily in Neocortical Neurons and May Play No Role in Delivering Glutamine for Glutamatergic Transmission

Grewal

Defamie

Zhang

et al. 2009

Journal of Biological Chemistry

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System A transporters SNAT1 and SNAT2 mediate uptake of neutral ␣-amino acids (e.g. glutamine, alanine, and proline) and are expressed in central neurons. We tested the hypothesis that SNAT2 is required to support neurotransmitter glutamate synthesis by examining spontaneous excitatory activity after inducing or repressing SNAT2 expression for prolonged periods. We stimulated de novo synthesis of SNAT2 mRNA and increased SNAT2 mRNA stability and total SNAT2 protein and functional activity, whereas SNAT1 expression was unaffected. Increased endogenous SNAT2 expression did not affect spontaneous excitatory action-potential frequency over control. Long term glutamine exposure strongly repressed SNAT2 expression but increased excitatory actionpotential frequency. Quantal size was not altered following SNAT2 induction or repression. These results suggest that spontaneous glutamatergic transmission in pyramidal neurons does not rely on SNAT2. To our surprise, repression of SNAT2 activity was not limited to System A substrates. Taurine, ␥-aminobutyric acid, and ␤-alanine (substrates of the SLC6 ␥-aminobutyric acid transporter family) repressed SNAT2 expression more potently (10؋) than did System A substrates; however, the responses to System A substrates were more rapid. Since ATF4 (activating transcription factor 4) and CCAAT/enhancer-binding protein are known to bind to an amino acid response element within the SNAT2 promoter and mediate induction of SNAT2 in peripheral cell lines, we tested whether either factor was similarly induced by amino acid deprivation in neurons. We found that glutamine and taurine repressed the induction of both transcription factors. Our data revealed that SNAT2 expression is constitutively low in neurons under physiological conditions but potently induced, together with the taurine transporter TauT, in response to depletion of neutral amino acids.Central neurons express the sodium-coupled neutral amino acid transporters SNAT1 and SNAT2 (also known as SLC38A1, GlnT, SAT1, or ATA1 and SLC38A2, SAT2, or ATA2, respectively) (1-10), two of the three SLC38 gene family members (reviewed in Ref. 11) that collectively account for the System A amino acid transport activity classically described in most cell types (12, 13). System A catalyzes the unidirectional uptake of small aliphatic neutral amino acids, especially alanine, cysteine, glutamine, glycine, methionine, proline, and serine. Among these, glutamine is around 10-fold more abundant than any other amino acid in extraneuronal space (14 -16), which, combined with the high affinity of System A transporters for glutamine (K m ϭ 0.2-0.5 mM), makes glutamine the predominant substrate for System A in neurons of the brain. Glutamine, in addition to glucose, is a major precursor for glutamate (17), and many neuronal cell bodies in the brain express phosphate-activated glutaminase (18,19) and contain high levels of glutamate. Whereas System N transporters may serve the exodus of glutamine from the astrocyte (9,20,21), these observations present the ...

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Selective tonicity-induced expression of the neutral amino-acid transporter SNAT2 in oligodendrocytes in rat brain following systemic hypertonicity

Cited by 19 publications

References 52 publications

Transcriptomic responses to sodium chloride‐induced osmotic stress: A study of industrial fed‐batch CHO cell cultures

Transcriptomic responses to sodium chloride‐induced osmotic stress: A study of industrial fed‐batch CHO cell cultures

Gap junctions favor normal rat kidney epithelial cell adaptation to chronic hypertonicity

SNAT2 Amino Acid Transporter Is Regulated by Amino Acids of the SLC6 γ-Aminobutyric Acid Transporter Subfamily in Neocortical Neurons and May Play No Role in Delivering Glutamine for Glutamatergic Transmission

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