Complementary expression of SN1 and SAT2 in the islets of Langerhans suggests concerted action of glutamine transport in the regulation of insulin secretion

Gammelsaeter, Runhild; Jenstad, Monica; Bredahl, May Kristin Lyamouri; Gundersen, Vidar; Chaudhry, Farrukh A.

doi:10.1016/j.bbrc.2009.02.062

Cited by 27 publications

(26 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A broad band close to 50 kDa, resembling the reported band for SN1 in brain, kidney, and pancreas tissue (Boulland et al, 2002(Boulland et al, , 2003Solbu et al, 2005;Gammelsaeter et al, 2009), was seen before PMA stimulation. A time course of PMA stimulation shows a gradual reduction in the staining of this band and the simultaneous appearance of a broad band of ϳ40 kDa, which probably represents degraded SN1 (Fig.…”

Section: Prolonged Activation Of Pkc Results In Degradation Of Sn1supporting

confidence: 68%

“…The different PKC isoforms yield specificity in time and space and convey divergence in signaling cascades. SN1 is involved in transmitter generation and nitrogen metabolism and shows a highly differential cellular and subcellular localization (Chaudhry et al, 1999;Boulland et al, 2002;Gammelsaeter et al, 2009). Together with the previously demonstrated regulation of SN1 at protein and mRNA level (Chaudhry et al, 2001;Solbu et al, 2005), the current demonstration of phosphorylation of rat SN1 by two PKC isoforms targeting a single residue in the N terminal adds a new dimension to the complex regulation of SN1.…”

Section: Resultssupporting

confidence: 54%

“…These isoforms are active in brain tissue, glioma cells, hepatocytes, pancreatic B-cells, kidney cells, and skeletal muscle cells (Huang et al, 1988;Croquet et al, 1996;Tian et al, 1996;Pfaff et al, 1999;Sneddon et al, 2000;Acevedo-Duncan et al, 2004;Gonzalez et al, 2005). The same cells also express SN1 (Boulland et al, 2002;Gu et al, 2005;Onan et al, 2005;Solbu et al, 2005;Gammelsaeter et al, 2009). Indeed, intracellular SN1-stained vesicle-like structures have been demonstrated in glial and kidney tubular cells, underpinning SN1 trafficking (Boulland et al, 2003;Solbu et al, 2005).…”

Section: Discussionmentioning

confidence: 92%

See 2 more Smart Citations

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Nissen‐Meyer¹,

Popescu²,

Hamdani³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

Molecular mechanisms involved in the replenishment of the fast neurotransmitters glutamate and GABA are poorly understood. Glutamine sustains their generation. However, glutamine formation from the recycled transmitters is confined to glial processes and requires facilitators for its translocation across the glial and neuronal membranes. Indeed, glial processes are enriched with the system N transporter SN1 (Slc38a3), which, by bidirectional transport, maintains steady extracellular glutamine levels and thereby furnishes neurons with the primary precursor for fast neurotransmitters. We now demonstrate that SN1 is phosphorylated by protein kinase C␣ (PKC␣) and PKC␥. Electrophysiological characterization shows that phosphorylation reduces V max dramatically, whereas no significant effects are seen on the K m . Phosphorylation occurs specifically at a single serine residue (S52) in the N-terminal rat (Rattus norvegicus) SN1 and results in sequestration of the protein into intracellular reservoirs. Prolonged activation of PKC results in partial degradation of SN1. These results provide the first demonstration of phosphorylation of SN1 and regulation of its activity at the plasma membrane. Interestingly, membrane trafficking of SN1 resembles that of the glutamate transporter GLT and the glutamate-aspartate transporter GLAST: it involves the same PKC isoforms and occurs in the same glial processes. This suggests that the glutamate/GABA-glutamine cycle may be modified at two key points by similar signaling events and unmasks a prominent role for PKC-dependent phosphorylation. Our data suggest that extracellular glutamine levels may be fine-tuned by dynamic regulation of glial SN1 activity, which may impact on transmitter generation, contribute to defining quantal size, and have profound effects on synaptic plasticity.

show abstract

Section: Prolonged Activation Of Pkc Results In Degradation Of Sn1supporting

confidence: 68%

Section: Resultssupporting

confidence: 54%

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Nissen‐Meyer¹,

Popescu²,

Hamdani³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Our findings and recent reports indicate that ␣-cells express a functional glutamine uptake system (ASCT2 and SAT2) (53) and a phosphate-dependent glutaminase activity; thus, consequently intracellular glutamate in the ␣-cell may be prevalently derived from glutamine transamination (54).…”

Section: Discussionsupporting

confidence: 69%

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

Cairano

Davalli

Perego

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Glutamate is the major excitatory neurotransmitter of the central nervous system (CNS) and may induce cytotoxicity through persistent activation of glutamate receptors and oxidative stress. Its extracellular concentration is maintained at physiological concentrations by high affinity glutamate transporters of the solute carrier 1 family (SLC1). Glutamate is also present in islet of Langerhans where it is secreted by the ␣-cells and acts as a signaling molecule to modulate hormone secretion. Whether glutamate plays a role in islet cell viability is presently unknown. We demonstrate that chronic exposure to glutamate exerts a cytotoxic effect in clonal ␤-cell lines and human islet ␤-cells but not in ␣-cells. In human islets, glutamate-induced ␤-cell cytotoxicity was associated with increased oxidative stress and led to apoptosis and autophagy. We also provide evidence that the key regulator of extracellular islet glutamate concentration is the glial glutamate transporter 1 (GLT1). GLT1 localizes to the plasma membrane of ␤-cells, modulates hormone secretion, and prevents glutamate-induced cytotoxicity as shown by the fact that its down-regulation induced ␤-cell death, whereas GLT1 up-regulation promoted ␤-cell survival. In conclusion, the present study identifies GLT1 as a new player in glutamate homeostasis and signaling in the islet of Langerhans and demonstrates that ␤-cells critically depend on its activity to control extracellular glutamate levels and cellular integrity.

show abstract

“…Glutamine transport in the liver and in pancreatic ␤-cells is mediated by SNAT3 (12,53). Exposure to glutamine causes hepatocytes to swell (54) and ␤-cells to depolarize (55).…”

Section: Discussionmentioning

confidence: 99%

Mutation of Asparagine 76 in the Center of Glutamine Transporter SNAT3 Modulates Substrate-induced Conductances and Na+ Binding

Bröer

Schneider

Deitmer

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The glutamine transporter SLC38A3 (SNAT3) plays an important role in the release of glutamine from brain astrocytes and the uptake of glutamine into hepatocytes. It is related to the vesicular GABA (␥-aminobutyric acid) transporter and the SLC36 family of proton-amino acid cotransporters. The transporter carries out electroneutral Na ؉ -glutamine cotransport-H ؉ antiport. In addition, substrate-induced uncoupled cation currents are observed. Mutation of asparagine 76 to glutamine or histidine in predicted transmembrane helix 1 abolished all substrate-induced currents. Mutation of asparagine 76 to aspartate rendered the transporter Na ؉ -independent and resulted in a gain of a large substrate-induced chloride conductance in the absence of Na ؉ . Thus, a single residue is critical for coupled and uncoupled ion flows in the glutamine transporter SNAT3. Homology modeling of SNAT3 along the structure of the related benzyl-hydantoin permease from Microbacterium liquefaciens reveals that Asn-76 is likely to be located in the center of the membrane close to the translocation pore and forms part of the predicted Na ؉ -binding site.The amino acid and auxin permease superfamily comprises a wide variety of transport proteins. In mammals, three distinct solute carrier families (SLC) belong to this superfamily, namely SLC32, SLC36, and SLC38 (1). Despite belonging to the same superfamily, the three solute carrier families have different transport mechanisms. The SLC32 family has only one member, the vesicular inhibitory amino acid transporter, which supposedly carries out a H ϩ -GABA (␥-aminobutyric acid) antiport (2). The SLC36 family comprises four members, two of which have been characterized in more detail. These are the proton amino acid cotransporters 1 and 2 (PAT1 and 2) that carry out glycine and proline uptake in kidney and intestine and are mutated in iminoglycinuria (3, 4). The SLC38 family is comprised of 11 members, 5 of which have been characterized in more detail (5). Two different transport mechanisms are found within this family, namely the Na ϩ -amino acid cotransporters SNAT1, SNAT2, and SNAT4 and the Na ϩ -amino acid cotransporters-H ϩ -antiporters SNAT3 and SNAT5. Transporters of the superfamily play a key role in inhibitory and excitatory neurotransmission, metabolite absorption, and liver metabolism. Despite their important roles in mammalian physiology, relatively little is known about the structure and function of these transporters.The activity of ion-coupled membrane transporters is frequently associated with currents which de-or hyperpolarize the cell membrane. These currents may be due to electrogenic transport stoichiometry and/or to a non-stoichiometric ion conductance (6). Transport-associated ion conductances have been identified in a number of transporters but have been particularly well studied in several Na ϩ -coupled neurotransmitter transporters (7-11). Transport-associated conductances have also been observed in electroneutral transporters that do not carry out net charge movement (8,(12...

show abstract

Complementary expression of SN1 and SAT2 in the islets of Langerhans suggests concerted action of glutamine transport in the regulation of insulin secretion

Cited by 27 publications

References 38 publications

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

Mutation of Asparagine 76 in the Center of Glutamine Transporter SNAT3 Modulates Substrate-induced Conductances and Na+ Binding

Contact Info

Product

Resources

About