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Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.
Dean ED, Li M, Prasad N, Wisniewski SN, Von Deylen A, Spaeth J, Maddison L, Botros A, Sedgeman LR, Bozadjieva N, Ilkayeva O, Coldren A, Poffenberger G, Shostak A, Semich MC, Aamodt KI, Phillips N, Yan H, Bernal-Mizrachi E, Corbin JD, Vickers KC, Levy SE, Dai C, Newgard C, Gu W, Stein R, Chen W, Powers AC
(2017) Cell Metab 25: 1362-1373.e5
MeSH Terms: Amino Acid Transport Systems, Neutral, Animals, Cell Proliferation, Glucagon, Glutamine, Liver, Mice, Mice, Knockout, Signal Transduction, Zebrafish, Zebrafish Proteins
Show Abstract · Added September 21, 2018
Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human α cells was mTOR and FoxP transcription factor dependent. Changes in hepatic amino acid (AA) catabolism gene expression predicted the observed increase in circulating AAs. Mimicking these AA levels stimulated α cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. α cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in α cell proliferation. These results indicate a hepatic α islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate α cell proliferation and mass via mTOR-dependent nutrient sensing.
Copyright © 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants.
Fike CD, Summar M, Aschner JL
(2014) Acta Paediatr 103: 1019-26
MeSH Terms: Amino Acid Transport Systems, Neutral, Animals, Cardiovascular Diseases, Citrulline, Endothelial Cells, Humans, Hypertension, Pulmonary, Hypoxia, Infant, Newborn, Models, Animal, Nitric Oxide, Nitric Oxide Synthase Type III
Show Abstract · Added February 19, 2015
UNLABELLED - Effective therapies are urgently needed for infants with forms of pulmonary hypertension that develop or persist beyond the first week of life. The L-arginine nitric oxide (NO) precursor, L-citrulline, improves NO signalling and ameliorates pulmonary hypertension in newborn animals. In vitro studies demonstrate that manipulating L-citrulline transport alters NO production.
CONCLUSION - Strategies that increase the supply and transport of L-citrulline merit pursuit as novel approaches to managing infants with chronic, progressive pulmonary hypertension.
©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.
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12 MeSH Terms
Effects of typical and atypical antipsychotics on human glycine transporters.
Williams JB, Mallorga PJ, Conn PJ, Pettibone DJ, Sur C
(2004) Schizophr Res 71: 103-12
MeSH Terms: Amino Acid Transport Systems, Neutral, Animals, Antipsychotic Agents, Benzodiazepines, Brain, Chloride Channels, Choriocarcinoma, Clozapine, Female, Glycine, Glycine Plasma Membrane Transport Proteins, Haloperidol, Humans, Membrane Glycoproteins, Membrane Transport Modulators, Membrane Transport Proteins, Olanzapine, Rats, Receptors, N-Methyl-D-Aspartate, Risperidone, Schizophrenia, Sodium Channels, Synapses, Uterine Neoplasms
Show Abstract · Added February 19, 2015
Augmentation strategy in the treatment of schizophrenia with the NMDA receptor co-agonist glycine has demonstrated significant improvement in patient symptoms. Interestingly, the therapeutic efficacy of glycine was more consistent among patients that were not co-administered clozapine suggesting that clozapine modulates glycine levels in brain. Since cerebral glycine concentration in the vicinity of NMDA receptors is thought to be controlled by the glia expressed glycine transporter type 1 (GlyT1), the effects of several typical and atypical antipsychotics on glycine uptake were examined in human placenta choriocarcinoma (JAR) cells expressing human GlyT1a. The selectivity of these compounds was investigated by measuring their inhibitory potency at the closely related glycine transporter type 2 (GlyT2). Typical antipsychotics haloperidol, thioridazine and chlorpromazine non-selectively inhibited [(14)C]glycine uptake mediated by GlyT1a and GlyT2 with potency of 9-21 microM. The atypical antipsychotic, clozapine antagonized glycine transport by human GlyT1a with an IC(50) of 100 microM and was weaker at recombinant GlyT2. Its main metabolites, N-desmethylclozapine and clozapine N-oxide were very weak inhibitors at all glycine transporters. Similarly, olanzapine did not potently block GlyT1a- and GlyT2-mediated uptake. Detailed kinetic analysis of hGlyT1a in the presence and absence of haloperidol and clozapine revealed that both drugs were not competitive inhibitors of glycine uptake. Data also indicated that these compounds did not interact with the Na(+) and Cl(-) sites of hGlyT1a. Our results have revealed the existence of an inhibitory interaction between some antipsychotics and hGlyT1a and raise the possibility that these drugs could interact with GlyT1 function at therapeutic doses.
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24 MeSH Terms
Development of a scintillation proximity assay for analysis of Na+/Cl- -dependent neurotransmitter transporter activity.
Williams JB, Mallorga PJ, Lemaire W, Williams DL, Na S, Patel S, Conn PJ, Conn JP, Pettibone DJ, Austin C, Sur C
(2003) Anal Biochem 321: 31-7
MeSH Terms: Amino Acid Transport Systems, Neutral, Carbon Radioisotopes, Cell Count, Cell Line, Tumor, Chlorides, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Neoplastic, Glycine, Glycine Plasma Membrane Transport Proteins, Humans, Pregnancy, Scintillation Counting, Sodium, Taurine, Time Factors
Show Abstract · Added February 19, 2015
Human placental choriocarcinoma (JAR) cells endogenously expressing glycine transporter type 1a (GlyT1a) have been cultured in 96-well scintillating microplates to develop a homogenous screening assay for the detection of GlyT1 antagonists. In these microplates uptake of [14C]glycine was time dependent and saturable with a Michaelis-Menten constant (Km) of 27+/-3 microM. The GlyT1 transport inhibitors sarcosine, ALX-5407, and Org-24598 were tested and shown to block [14C]glycine uptake with expected IC50 values of 37.5+/-4.6 microM, 2.8+/-0.6 nM, and 6.9+/-0.9 nM, respectively. The [14C]glycine uptake process was sensitive to membrane Na+ gradient as blockade of membrane Na+/K+-ATPase by ouabain or Na+ exchanger by benzamil-disrupted glycine accumulation in JAR cells. Glycine influx was not affected by concentration of dimethyl sulfoxide up to 2%. The versatility of this technological approach was further confirmed by the characterization of a saturable [14C]taurine uptake in JAR cells. Taurine transport was of high affinity with a Km of 10.2+/-1.7 microM and fully inhibited by ALX-5407 (IC50=522 +/-83 nM). The developed assay is homogenous, rapid, versatile and amenable to automation for the discovery of new neurotransmitter transporter inhibitors.
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16 MeSH Terms
Pharmacology and expression analysis of glycine transporter GlyT1 with [3H]-(N-[3-(4'-fluorophenyl)-3-(4'phenylphenoxy)propyl])sarcosine.
Mallorga PJ, Williams JB, Jacobson M, Marques R, Chaudhary A, Conn PJ, Pettibone DJ, Sur C
(2003) Neuropharmacology 45: 585-93
MeSH Terms: Amino Acid Transport Systems, Neutral, Analysis of Variance, Animals, Binding, Competitive, Cell Line, Cell Membrane, Central Nervous System, Dose-Response Relationship, Drug, Glycine, Glycine Plasma Membrane Transport Proteins, Humans, Kinetics, Lithium Chloride, Radioligand Assay, Rats, Sarcosine, Sodium Acetate, Sodium Chloride, Time Factors, Tritium
Show Abstract · Added February 19, 2015
In the central nervous system, re-uptake of the neurotransmitter glycine is mediated by two different glycine transporters, GlyT1 and GlyT2. GlyT2 is found in brainstem and spinal cord, whereas GlyT1 is expressed in rat forebrain regions where it is responsible for most glycine transport activity. Initially, GlyT1 and GlyT2 were pharmacologically differentiated by sarcosine, a weak selective inhibitor of GlyT1. The recently described selective and potent GlyT1 antagonist, NFPS/ALX-5407 provided an important additional tool to further characterize GlyT1 pharmacology. In the present study, we have radiolabeled the racemic form of NFPS (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (also known as ALX-5407) to investigate its interaction with GlyT1, as well as define GlyT1 expression in the rat central nervous system. Kinetic studies indicated that [3H]NFPS binds rapidly to rat forebrain membranes and dissociates with a t(1/2) of 28 +/- 5 min. [3H]NFPS labeled a saturable population of sites in rat forebrain with a Kd of 7.1+/-1.3 nM and a B(max) of 3.14 +/- 0.26 pmol/mg protein. Bound [3H]NFPS was fully and potently displaced by unlabeled NFPS, whereas glycine and sarcosine were weak, Na+-dependent inhibitors with IC50 of 1,008 and 190 microM, respectively. Additional saturation experiments indicated that glycine and sarcosine were non-competitive antagonists of [3H]NFPS binding. Functional studies revealed that NFPS was a non-competitive inhibitor of [3H]glycine uptake and does not interact with Na+ and Cl- binding sites of GlyT1. Overall, this work shows that [3H]NFPS is a valuable tool in studying GlyT1 expression and pharmacology and that NFPS interacts with GlyT1 at a site different from the transporter translocation and ion binding sites.
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20 MeSH Terms
The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior.
Kinney GG, Sur C, Burno M, Mallorga PJ, Williams JB, Figueroa DJ, Wittmann M, Lemaire W, Conn PJ
(2003) J Neurosci 23: 7586-91
MeSH Terms: Amino Acid Transport Systems, Neutral, Animals, Antipsychotic Agents, Behavior, Animal, Biological Transport, Cell Line, Glycine, Glycine Plasma Membrane Transport Proteins, Humans, Long-Term Potentiation, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Neural Inhibition, Proto-Oncogene Proteins c-fos, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Sarcosine
Show Abstract · Added February 19, 2015
Glycine acts as a necessary coagonist for glutamate at the NMDA receptor (NMDAR) complex by binding to the strychnine-insensitive glycine-B binding site on the NR1 subunit. The fact that glycine is normally found in the brain and spinal cord at concentrations that exceed those required to saturate this site has led to the speculation that glycine normally saturates NMDAR-containing synapses in vivo. However, additional lines of evidence suggest that synaptic glycine may be efficiently regulated in synaptic areas by the glycine transporter type 1 (GlyT1). The recent description of a potent and selective GlyT1 inhibitor (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine [NFPS]) provides a tool for evaluation of the hypothesis that inhibition of GlyT1 may increase synaptic glycine and thereby potentiate NMDAR function in vivo. In the present study, we found that (+)-NFPS demonstrated >10-fold greater activity in an in vitro functional glycine reuptake assay relative to the racemic compound. In vivo, (+/-)-NFPS significantly enhanced long-term potentiation in the hippocampal dentate gyrus induced by high-frequency electrical stimulation of the afferent perforant pathway. Furthermore, (+)-NFPS induced a pattern of c-Fos immunoreactivity comparable with the atypical antipsychotic clozapine and enhanced prepulse inhibition of the acoustic startle response in DBA/2J mice, a strain with low basal levels of prepulse inhibition. Collectively, these data suggest that selective inhibition of GlyT1 can enhance NMDAR-sensitive activity in vivo and also support the idea that GlyT1 may represent a novel target for developing therapeutics to treat disorders associated with NMDAR hypofunction.
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20 MeSH Terms
A novel nonopioid action of enkephalins: competitive inhibition of the mammalian brain high affinity L-proline transporter.
Fremeau RT, Velaz-Faircloth M, Miller JW, Henzi VA, Cohen SM, Nadler JV, Shafqat S, Blakely RD, Domin B
(1996) Mol Pharmacol 49: 1033-41
MeSH Terms: Amino Acid Transport Systems, Neutral, Animals, Brain, Enkephalins, HeLa Cells, Humans, Male, Membrane Transport Modulators, Membrane Transport Proteins, Naltrexone, Proline, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship
Show Abstract · Added July 10, 2013
The high affinity L-proline transporter (PROT) is a member of the family of Na+ (and Cl-)-dependent plasma membrane transport proteins that comprises transporters for several neurotransmitters, osmolytes, and metabolites. The brain-specific expression of PROT in a subset of putative glutamatergic pathways implies a specialized function for this novel transporter and its presumed natural substrate L-proline in excitatory synaptic transmission. However, definitive studies of the physiological role(s) of high affinity L-proline uptake have been precluded by the lack of specific uptake inhibitors. Here, we report that Leu- and Met-enkephalin and their des-tyrosyl derivatives potently and selectively inhibited high affinity L-proline uptake in rat hippocampal synaptosomes and in PROT-transfected HeLa cells. High concentrations of the opiate receptor antagonist naltrexone did not block the inhibitory actions of these peptides, arguing against an involvement of opioid receptors. Des-tyrosyl-Leu-enkephalin elevated the apparent K(m) of L-proline transport in transfected HeLa cells without altering the V(max). PROT-transfected HeLa cells did not accumulate [3H]Leu-enkephalin above background levels, demonstrating that enkephalins are not substrates for PROT. These findings indicate that enkephalins competitively inhibit mammalian brain PROT through a direct interaction with the transporter protein at or near the L-proline binding site. The high potency and specificity of des-tyrosyl-Leu-enkephalin make this compound a useful tool for elucidating the structure-function properties and physiological role(s) of PROT.
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14 MeSH Terms
Molecular cloning and expression of a high affinity L-proline transporter expressed in putative glutamatergic pathways of rat brain.
Fremeau RT, Caron MG, Blakely RD
(1992) Neuron 8: 915-26
MeSH Terms: Amino Acid Sequence, Amino Acid Transport Systems, Neutral, Animals, Base Sequence, Blotting, Northern, Brain, Brain Chemistry, Carrier Proteins, Cloning, Molecular, Gene Expression, Glutamates, Glutamic Acid, HeLa Cells, Humans, Leucine Zippers, Molecular Sequence Data, Nucleic Acid Hybridization, Polymerase Chain Reaction, Proline, RNA, Messenger, Rats, Sodium, Transfection
Show Abstract · Added July 10, 2013
We have used the polymerase chain reaction (PCR) with degenerate oligonucleotides derived from two conserved regions of the norepinephrine and gamma-aminobutyric acid transporters to identify novel Na(+)-dependent transporters in rat brain. One PCR product hybridized to a 4.0 kb RNA concentrated in subpopulations of putative glutamatergic neurons including mitral cells of the olfactory bulb, pyramidal cells of layer V of the cerebral cortex, pyramidal cells of the piriform cortex, and pyramidal cells of field CA3 of the hippocampus. Transient expression of the cognate cDNA conferred Na(+)-dependent L-proline uptake in HeLa cells that was saturable (Km = 9.7 microM) and exhibited a pharmacological profile similar to that for high affinity L-proline transport in rat brain slices. The cloned transporter cDNA predicts a 637 aa protein with 12 putative transmembrane domains and exhibits 44%-45% amino acid sequence identity with other members of the emerging family of neurotransmitter transporters. These findings support a synaptic role for L-proline in specific excitatory pathways in the CNS.
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23 MeSH Terms