The amino acid transporters of the glutamate/GABA-glutamine cycle and their impact on insulin and glucagon secretion

Frontiers in Endocrinology

Volumn 4, Issue DEC, 2013, Pages

  Jenstad, Monica ^a,b   Chaudhry, Farrukh Abbas ^b  

^a OSLO UNIVERSITY HOSPITAL   (Norway)

^b UNIVERSITY OF OSLO   (Norway)

Author keywords

GABA; Glutamate; Glutamine; Insulin; SAT2; Slc38a2; Slc38a3; SN1

Indexed keywords

EID: 84892161340     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2013.00199     Document Type: Short Survey

References (90)

1. Hori Y, Gu X, Xie X, Kim SK. Differentiation of insulin-producing cells from human neural progenitor cells. PLoS Med (2005) 2:e103. doi:10.1371/journal.pmed.0020103.
2. Wang S, Tulina N, Carlin DL, Rulifson EJ. The origin of islet-like cells in Drosophila identifies parallels to the vertebrate endocrine axis. Proc Natl Acad Sci U S A (2007) 104:19873-8. doi:10.1073/pnas.0707465104.
3. Schwartz MW, Seeley RJ, Tschop MH, Woods SC, Morton GJ, Myers MG, et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature (2013) 503:59-66. doi:10.1038/nature12709.
4. Li C, Buettger C, Kwagh J, Matter A, Daikhin Y, Nissim IB, et al. A signaling role of glutamine in insulin secretion. J Biol Chem (2004) 279:13393-401. doi:10.1074/jbc.M311502200.
5. Gao ZY, Li G, Najafi H, Wolf BA, Matschinsky FM. Glucose regulation of glutaminolysis and its role in insulin secretion. Diabetes (1999) 48:1535-42. doi:10.2337/diabetes.48.8.1535.
6. Zawalich WS, Yamazaki H, Zawalich KC, Cline G. Comparative effects of amino acids and glucose on insulin secretion from isolated rat or mouse islets. J Endocrinol (2004) 183:309-19. doi:10.1677/joe.1.05832.
7. Maechler P, Wollheim CB. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature (1999) 402:685-9. doi:10.1038/45280.
8. Newsholme P, Brennan L, Rubi B, Maechler P. New insights into amino acid metabolism, β-cell function and diabetes. Clin Sci (2005) 108:185-94. doi:10.1042/CS20040290.
9. Martínez-Hernandez A, Bell KP, Norenberg MD. Glutamine synthetase: glial localization in brain. Science (1977) 195:1356-8. doi:10.1126/science.14400.
10. Haberle J, Shahbeck N, Ibrahim K, Schmitt B, Scheer I, O'Gorman R, et al. Glutamine supplementation in a child with inherited GS deficiency improves the clinical status and partially corrects the peripheral and central amino acid imbalance. Orphanet J Rare Dis (2012) 7:48. doi:10.1186/1750-1172-7-48.
11. Kvamme E, Torgner IA, Roberg B. Kinetics and localization of brain phosphate activated glutaminase. J Neurosci Res (2001) 66:951-8. doi:10.1002/jnr.10041.
12. Chaudhry FA, Boulland JL, Jenstad M, Bredahl MK, Edwards RH. Pharmacology of neurotransmitter transport into secretory vesicles. Handb Exp Pharmacol (2008) 184:77-106. doi:10.1007/978-3-540-74805-2_4.
13. Chaudhry FA, Lehre KP, van Lookeren CM, Ottersen OP, Danbolt NC, Storm-Mathisen J. Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron (1995) 15:711-20. doi:10.1016/0896-6273(95)90158-2.
14. Chaudhry FA, Reimer RJ, Bellocchio EE, Danbolt NC, Osen KK, Edwards RH, et al. The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J Neurosci (1998) 18:9733-50.
15. Fremeau RT Jr, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, et al. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron (2001) 31:247-60. doi:10.1016/S0896-6273(01)00344-0.
16. Boulland JL, Qureshi T, Seal RP, Rafiki A, Gundersen V, Bergersen LH, et al. Expression of the vesicular glutamate transporters during development indicates the widespread corelease of multiple neurotransmitters. J Comp Neurol (2004) 480:264-80. doi:10.1002/cne.20354.
17. Rowley NM, Madsen KK, Schousboe A, Steve White H. Glutamate and GABA synthesis, release, transport and metabolism as targets for seizure control. Neurochem Int (2012) 61:546-58. doi:10.1016/j.neuint.2012.02.013.
18. Chaudhry FA, Reimer RJ, Krizaj D, Barber D, Storm-Mathisen J, Copenhagen DR, et al. Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Cell (1999) 99:769-80. doi:10.1016/S0092-8674(00)81674-8.
19. Chaudhry FA, Schmitz D, Reimer RJ, Larsson P, Gray AT, Nicoll R, et al. Glutamine uptake by neurons: interaction of protons with system A transporters. J Neurosci (2002) 22:62-72.
20. Albrecht J, Sidoryk-Wegrzynowicz M, Zielinska M, Aschner M. Roles of glutamine in neurotransmission. Neuron Glia Biol (2010) 6:263-76. doi:10.1017/S1740925X11000093.
21. Chaudhry FA, Krizaj D, Larsson P, Reimer RJ, Wreden C, Storm-Mathisen J, et al. Coupled and uncoupled proton movement by amino acid transport system N. EMBO J (2001) 20:7041-51. doi:10.1093/emboj/20.24.7041.
22. Hamdani EH, Gudbrandsen M, Bjørkmo M, Chaudhry FA. The system N transporter SN2 doubles as a transmitter precursor furnisher and a potential regulator of NMDA receptors. Glia (2012) 60:1671-83. doi:10.1002/glia.22386.
23. Jenstad M, Quazi AZ, Zilberter M, Haglerød C, Berghuis P, Saddique N, et al. System A transporter SAT2 mediates replenishment of dendritic glutamate pools controlling retrograde signaling by glutamate. Cereb Cortex (2009) 19:1092-106. doi:10.1093/cercor/bhn151.
24. Solbu TT, Bjørkmo M, Berghuis P, Harkany T, Chaudhry FA. SAT1, a glutamine transporter, is preferentially expressed in GABAergic neurons. Front Neuroanat (2010) 4:1. doi:10.3389/neuro.05.001.2010.
25. Liang SL, Carlson GC, Coulter DA. Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1. J Neurosci (2006) 26:8537-48. doi:10.1523/JNEUROSCI.0329-06.2006.
26. Fricke MN, Jones-Davis DM, Mathews GC. Glutamine uptake by system A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission. J Neurochem (2007) 102:1895-904. doi:10.1111/j.1471-4159.2007.04649.x.
27. Solbu TT, Boulland JL, Zahid W, Lyamouri Bredahl MK, Amiry-Moghaddam M, Storm-Mathisen J, et al. Induction and targeting of the glutamine transporter SN1 to the basolateral membranes of cortical kidney tubule cells during chronic metabolic acidosis suggest a role in pH regulation. J Am Soc Nephrol (2005) 16:869-77. doi:10.1681/ASN.2004060433.
28. Gu S, Villegas CJ, Jiang JX. Differential regulation of amino acid transporter SNAT3 by insulin in hepatocytes. J Biol Chem (2005) 280:26055-62. doi:10.1074/jbc.M504401200.
29. Bröer S. The SLC38 family of sodium-amino acid co-transporters. Pflugers Arch (2013). doi:10.1007/s00424-013-1393-y. [Epub ahead of print].
30. Arntfield ME, van der Kooy D. β-Cell evolution: how the pancreas borrowed from the brain: the shared toolbox of genes expressed by neural and pancreatic endocrine cells may reflect their evolutionary relationship. Bioessays (2011) 33:582-7. doi:10.1002/bies.201100015.
31. van Arensbergen J, García-Hurtado J, Moran I, Maestro MA, Xu X, Van de Casteele M, et al. Derepression of polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program. Genome Res (2010) 20:722-32. doi:10.1101/gr.101709.109.
32. Xie Q, Yang Y, Huang J, Ninkovic J, Walcher T, Wolf L, et al. Pax6 interactions with chromatin and identification of its novel direct target genes in lens and forebrain. PLoS One (2013) 8:e54507. doi:10.1371/journal.pone.0054507.
33. Jensen J. Gene regulatory factors in pancreatic development. Dev Dyn (2004) 229:176-200. doi:10.1002/dvdy.10460.
34. Müller M, Jabs N, Lorke DE, Fritzsch B, Sander M. Nkx6.1 controls migration and axon pathfinding of cranial branchio-motoneurons. Development (2003) 130:5815-26. doi:10.1242/dev.00815.
35. Ahnert-Hilger G, Stadtbaumer A, Strubing C, Scherubl H, Schultz G, Riecken EO, et al. γ-Aminobutyric acid secretion from pancreatic neuroendocrine cells. Gastroenterology (1996) 110:1595-604. doi:10.1053/gast.1996.v110.pm8613067.
36. Thomas-Reetz AC, De Camilli P. A role for synaptic vesicles in non-neuronal cells: clues from pancreatic β cells and from chromaffin cells. FASEB J (1994) 8:209-16.
37. + channels in pancreatic beta cells: role, regulation and potential as therapeutic targets. Diabetologia (2003) 46:1046-62. doi:10.1007/s00125-003-1159-8.
38. Proks P, Lippiat JD. Membrane ion channels and diabetes. Curr Pharm Des (2006) 12:485-501. doi:10.2174/138161206775474431.
39. + channels: tuning β-cell excitability with syntaxin-1A and other exocytotic proteins. Endocr Rev (2007) 28:653-63. doi:10.1210/er.2007-0010.
40. Baroukh NN, Van Obberghen E. Function of microRNA-375 and microRNA-124a in pancreas and brain. FEBS J (2009) 276:6509-21. doi:10.1111/j.1742-4658.2009.07353.x.
41. Suckow AT, Craige B, Faundez V, Cain WJ, Chessler SD. An AP-3-dependent mechanism drives synaptic-like microvesicle biogenesis in pancreatic islet β-cells. Am J Physiol Endocrinol Metab (2010) 299:E23-32. doi:10.1152/ajpendo.00664.2009.
42. Hayashi M, Yamada H, Uehara S, Morimoto R, Muroyama A, Yatsushiro S, et al. Secretory granule-mediated co-secretion of L-glutamate and glucagon triggers glutamatergic signal transmission in islets of Langerhans. J Biol Chem (2003) 278:1966-74. doi:10.1074/jbc.M206758200.
43. Gammelsæter R, Coppola T, Marcaggi P, Storm-Mathisen J, Chaudhry FA, Attwell D, et al. A role for glutamate transporters in the regulation of insulin secretion. PLoS One (2011) 6:e22960. doi:10.1371/journal.pone.0022960.
44. Gonoi T, Mizuno N, Inagaki N, Kuromi H, Seino Y, Miyazaki J, et al. Functional neuronal ionotropic glutamate receptors are expressed in the non-neuronal cell line MIN6. J Biol Chem (1994) 269:16989-92.
45. Morley P, MacLean S, Gendron TF, Small DL, Tremblay R, Durkin JP, et al. Pharmacological and molecular characterization of glutamate receptors in the MIN6 pancreatic beta-cell line. Neurol Res (2000) 22:379-85.
46. Brice NL, Varadi A, Ashcroft SJ, Molnar E. Metabotropic glutamate and GABAB receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells. Diabetologia (2002) 45:242-52. doi:10.1007/s00125-001-0750-0.
47. Cabrera O, Jacques-Silva MC, Speier S, Yang SN, Kohler M, Fachado A, et al. Glutamate is a positive autocrine signal for glucagon release. Cell Metab (2008) 7:545-54. doi:10.1016/j.cmet.2008.03.004.
48. Braun M, Wendt A, Birnir B, Broman J, Eliasson L, Galvanovskis J, et al. Regulated exocytosis of GABA-containing synaptic-like microvesicles in pancreatic β-cells. J Gen Physiol (2004) 123:191-204. doi:10.1085/jgp.200308966.
49. Braun M, Ramracheya R, Bengtsson M, Clark A, Walker JN, Johnson PR, et al. γ-Aminobutyric acid (GABA) is an autocrine excitatory transmitter in human pancreatic β-cells. Diabetes (2010) 59:1694-701. doi:10.2337/db09-0797.
50. A-receptor chloride channels. Nature (1989) 341:233-6. doi:10.1038/341233a0.
51. Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, et al. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab (2006) 3:47-58. doi:10.1016/j.cmet.2005.11.015.
52. Kim J, Richter W, Aanstoot HJ, Shi Y, Fu Q, Rajotte R, et al. Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets. Diabetes (1993) 42:1799-808. doi:10.2337/diab.42.12.1799.
53. Anno T, Uehara S, Katagiri H, Ohta Y, Ueda K, Mizuguchi H, et al. Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation. Am J Physiol Endocrinol Metab (2004) 286:E280-5. doi:10.1152/ajpendo.00380.2003.
54. Garry DJ, Sorenson RL, Coulter HD. Ultrastructural localization of gamma amino butyric acid immunoreactivity in B cells of the rat pancreas. Diabetologia (1987) 30:115-9.
55. Gammelsæter R, Froyland M, Aragón C, Danbolt NC, Fortin D, Storm-Mathisen J, et al. Glycine, GABA and their transporters in pancreatic islets of Langerhans: evidence for a paracrine transmitter interplay. J Cell Sci (2004) 117:3749-58. doi:10.1242/jcs.01209.
56. Thorens B, Sarkar HK, Kaback HR, Lodish HF. Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney, and β-pancreatic islet cells. Cell (1988) 55:281-90. doi:10.1016/0092-8674(88)90051-7.
57. Maechler P. Mitochondrial function and insulin secretion. Mol Cell Endocrinol (2013) 379:12-8. doi:10.1016/j.mce.2013.06.019.
58. Carobbio S, Frigerio F, Rubi B, Vetterli L, Bloksgaard M, Gjinovci A, et al. Deletion of glutamate dehydrogenase in β-cells abolishes part of the insulin secretory response not required for glucose homeostasis. J Biol Chem (2009) 284:921-9. doi:10.1074/jbc.M806295200.
59. Vetterli L, Carobbio S, Pournourmohammadi S, Martin-Del-Rio R, Skytt DM, Waagepetersen HS, et al. Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase. Mol Biol Cell (2012) 23:3851-62. doi:10.1091/mbc.E11-08-0676.
60. Barker CJ, Leibiger IB, Berggren PO. The pancreatic islet as a signaling hub. Adv Biol Regul (2013) 53:156-63. doi:10.1016/j.jbior.2012.09.011.
61. Caicedo A. Paracrine and autocrine interactions in the human islet: more than meets the eye. Semin Cell Dev Biol (2013) 24:11-21. doi:10.1016/j.semcdb.2012.09.007.
62. Hnasko TS, Edwards RH. Neurotransmitter corelease: mechanism and physiological role. Annu Rev Physiol (2012) 74:225-43. doi:10.1146/annurev-physiol-020911-153315.
63. McIntire SL, Reimer RJ, Schuske K, Edwards RH, Jorgensen EM. Identification and characterization of the vesicular GABA transporter. Nature (1997) 389:870-6. doi:10.1038/39908.
64. Jonas P, Bischofberger J, Sandkühler J. Corelease of two fast neurotransmitters at a central synapse. Science (1998) 281:419-24. doi:10.1126/science.281.5375.419.
65. Chaudhry FA, Edwards RH, Fonnum F. Vesicular neurotransmitter transporters as targets for endogenous and exogenous toxic substances. Annu Rev Pharmacol Toxicol (2008) 48:277-301. doi:10.1146/annurev.pharmtox.46.120604.141146.
66. Boulland JL, Jenstad M, Boekel AJ, Wouterlood FG, Edwards RH, Storm-Mathisen J, et al. Vesicular glutamate and GABA transporters sort to distinct sets of vesicles in a population of presynaptic terminals. Cereb Cortex (2009) 19:241-8. doi:10.1093/cercor/bhn077.
67. Stensrud MJ, Chaudhry FA, Leergaard TB, Bjaalie JG, Gundersen V. Vesicular glutamate transporter-3 in the rodent brain: vesicular colocalization with vesicular γ-aminobutyric acid transporter. J Comp Neurol (2013) 521:3042-56. doi:10.1002/cne.23331.
68. El Mestikawy S, Wallén-Mackenzie A, Fortin GM, Descarries L, Trudeau LE. From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci (2011) 12:204-16. doi:10.1038/nrn2969.
69. Hayashi M, Morimoto R, Yamamoto A, Moriyama Y. Expression and localization of vesicular glutamate transporters in pancreatic islets, upper gastrointestinal tract, and testis. J Histochem Cytochem (2003) 51:1375-90. doi:10.1177/002215540305101014.
70. Hayashi M, Otsuka M, Morimoto R, Muroyama A, Uehara S, Yamamoto A, et al. Vesicular inhibitory amino acid transporter is present in glucagon-containing secretory granules in aαTC6 cells, mouse clonal α-cells, and α-cells of islets of Langerhans. Diabetes (2003) 52:2066-74. doi:10.2337/diabetes.52.8.2066.
71. Chessler SD, Simonson WT, Sweet IR, Hammerle LP. Expression of the vesicular inhibitory amino acid transporter in pancreatic islet cells: distribution of the transporter within rat islets. Diabetes (2002) 51:1763-71. doi:10.2337/diabetes.51.6.1763.
72. Suckow AT, Sweet IR, Van Yserloo B, Rutledge EA, Hall TR, Waldrop M, et al. Identification and characterization of a novel isoform of the vesicular γ-aminobutyric acid transporter with glucose-regulated expression in rat islets. J Mol Endocrinol (2006) 36:187-99. doi:10.1677/jme.1.01866.
73. Bai L, Zhang X, Ghishan FK. Characterization of vesicular glutamate transporter in pancreatic α-and β-cells and its regulation by glucose. Am J Physiol Gastrointest Liver Physiol (2003) 284:G808-14. doi:10.1152/ajpgi.00333.2002.
74. Feldmann N, del Rio RM, Gjinovci A, Tamarit-Rodriguez J, Wollheim CB, Wiederkehr A. Reduction of plasma membrane glutamate transport potentiates insulin but not glucagon secretion in pancreatic islet cells. Mol Cell Endocrinol (2011) 338:46-57. doi:10.1016/j.mce.2011.02.019.
75. Hatakeyama H, Takahashi N, Kishimoto T, Nemoto T, Kasai H. Two cAMP-dependent pathways differentially regulate exocytosis of large dense-core and small vesicles in mouse β-cells. J Physiol (2007) 582:1087-98. doi:10.1113/jphysiol.2007.135228.
76. Weaver CD, Gundersen V, Verdoorn TA. A high affinity glutamate/aspartate transport system in pancreatic islets of Langerhans modulates glucose-stimulated insulin secretion. J Biol Chem (1998) 273:1647-53. doi:10.1074/jbc.273.3.1647.
77. Di Cairano ES, Davalli AM, Perego L, Sala S, Sacchi VF, La RS, et al. The glial glutamate transporter 1 (GLT1) is expressed by pancreatic β-cells and prevents glutamate-induced β-cell death. J Biol Chem (2011) 286:14007-18. doi:10.1074/jbc.M110.183517.
78. Orci L, Ravazzola M, Amherdt M, Madsen O, Perrelet A, Vassalli JD, et al. Conversion of proinsulin to insulin occurs coordinately with acidification of maturing secretory vesicles. J Cell Biol (1986) 103:2273-81. doi:10.1083/jcb.103.6.2273.
79. - uptake and acidification. J Cell Sci (2001) 114:2145-54.
80. Deriy LV, Gomez EA, Jacobson DA, Wang X, Hopson JA, Liu XY, et al. The granular chloride channel ClC-3 is permissive for insulin secretion. Cell Metab (2009) 10:316-23. doi:10.1016/j.cmet.2009.08.012.
81. -/γ-aminobutyrate co-transporter. J Biol Chem (2009) 284:35073-8. doi:10.1074/jbc.M109.062414.
82. Omote H, Miyaji T, Juge N, Moriyama Y. Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. Biochemistry (2011) 50:5558-65. doi:10.1021/bi200567k.
83. Gammelsæter R, Jenstad M, Bredahl MK, Gundersen V, Chaudhry FA. Complementary expression of SN1 and SAT2 in the islets of Langerhans suggests concerted action of glutamine transport in the regulation of insulin secretion. Biochem Biophys Res Commun (2009) 381:378-82. doi:10.1016/j.bbrc.2009.02.062.
84. Bröer A, Albers A, Setiawan I, Edwards RH, Chaudhry FA, Lang F, et al. Regulation of the glutamine transporter SN1 by extracellular pH and intracellular sodium ions. J Physiol (2002) 539:3-14. doi:10.1113/jphysiol.2001.013303.
85. Schneider HP, Bröer S, Bröer A, Deitmer JW. Heterologous expression of the glutamine transporter SNAT3 in Xenopus oocytes is associated with four modes of uncoupled transport. J Biol Chem (2007) 282:3788-98. doi:10.1074/jbc.M609452200.
86. Gu S, Roderick HL, Camacho P, Jiang JX. Identification and characterization of an amino acid transporter expressed differentially in liver. Proc Natl Acad Sci U S A (2000) 97:3230-5. doi:10.1073/pnas.97.7.3230.
87. Nissen-Meyer LS, Popescu MC, Hamdani EH, Chaudhry FA. Protein kinase C-mediated phosphorylation of a single serine residue on the rat glial glutamine transporter SN1 governs its membrane trafficking. J Neurosci (2011) 31:6565-75. doi:10.1523/JNEUROSCI.3694-10.2011.
88. Malaisse WJ, Sener A, Carpinelli AR, Anjaneyulu K, Lebrun P, Herchuelz A, et al. The stimulus-secretion coupling of glucose-induced insulin release. XLVI. Physiological role of L-glutamine as a fuel for pancreatic islets. Mol Cell Endocrinol (1980) 20:171-89. doi:10.1016/0303-7207(80)90080-5.
89. Broca C, Brennan L, Petit P, Newsholme P, Maechler P. Mitochondria-derived glutamate at the interplay between branched-chain amino acid and glucose-induced insulin secretion. FEBS Lett (2003) 545:167-72. doi:10.1016/S0014-5793(03)00526-X.
90. Reimer RJ, Chaudhry FA, Gray AT, Edwards RH. Amino acid transport system A resembles system N in sequence but differs in mechanism. Proc Natl Acad Sci U S A (2000) 97:7715-20. doi:10.1073/pnas.140152797.