High Concentration of GABA and High Glutamate Decarboxylase Activity in Rat Pancreatic Islets and Human Insulinoma

Okada, Yasuhiro; Taniguchi, Hiroshi; Schimada, Chicaco

doi:10.1126/science.185693

Cited by 231 publications

(115 citation statements)

References 13 publications

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“…These results solve, at least in part, where, when, and how L-glutamate appears in the islets and what happens upon stimulation of glutamate receptors in the islets. Since evidence for a role of GABA as a paracrine signal transmitter in the islet has been reported (23)(24)(25)(26), these results also suggest the presence of L-glutamate-and GABA-mediated cross-talk between ␣ and ␤ cells in the islets of Langerhans.…”

supporting

confidence: 53%

Secretory Granule-mediated Co-secretion ofl-Glutamate and Glucagon Triggers Glutamatergic Signal Transmission in Islets of Langerhans

Hayashi

Yamada

Uehara

et al. 2003

Journal of Biological Chemistry

126

158

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L-Glutamate is the major excitatory neurotransmitter in the central nervous system and plays important roles in many neuronal processes such as fast synaptic transmission and neuronal plasticity (1, 2). To use L-glutamate as an intercellular signaling molecule, neuronal cells develop the glutamatergic system. Thus, L-glutamate is accumulated in synaptic vesicles through vesicular glutamate transporters (VGLUTs), 1 and is secreted through exocytosis. The released L-glutamate binds to the receptor so as to transmit signals intercellularly. The excess amount of L-glutamate in synaptic cleft is sequestrated through plasma membrane-type glutamate transporter. Recent evidence has indicated that peripheral non-neuronal tissues also possess the glutamatergic system and use L-glutamate as an intercellular transmitter (3). The islet of Langerhans, a pancreatic miniature organ for the hormones regulating the blood glucose level, is composed of four major types of endocrine cells, i.e. insulin-secreting ␤ cells, glucagon-secreting ␣ cells, somatostatin-secreting ␦ cells, and pancreatic polypeptide-secreting F cells. These islet cells expresses functional glutamate receptors and plasma membrane-type glutamate transporter (4 -11), suggesting that L-glutamate functions as an intercellular transmitter in islet. In fact, L-glutamate has been shown to affect secretion of insulin or glucagon from islet cells, isolated islets, or perfused pancreas (4 -11). However, the role of L-glutamate as an intercellular chemical transmitter in the islets has been long controversial, mainly because critical issues, i.e. where, when, and how L-glutamate appears in the islets and what happens upon stimulation of glutamate receptors in the islets, remain unresolved.Recent findings indicate that brain-specific Na ϩ -dependent inorganic phosphate cotransporter (12) and its isoform, differentiation-associated Na ϩ -dependent inorganic phosphate cotransporter (13), function as VGLUTs and are thus abbreviated as VGLUT1 and VGLUT2, respectively (14 -21). These VGLUTs seem to be potential probes for the site of L-glutamate release in peripheral tissues as well as the central nervous system since these transporters are essential for L-glutamate signal output. We have shown that VGLUT2 is expressed in ␣TC6 cells, clonal ␣ cells, and islet ␣ cells, but not in ␤ or ␦ cells (18). These results are consistent with the occurrence of Ca 2ϩ -dependent exocytosis of L-glutamate from ␣TC6 cells (22) and suggest that ␣ cells are the sites of L-glutamate signal appearance.During course of the study, we noticed that the expression and subcellular localization of VGLUTs are of extraordinary

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supporting

confidence: 53%

Secretory Granule-mediated Co-secretion ofl-Glutamate and Glucagon Triggers Glutamatergic Signal Transmission in Islets of Langerhans

Hayashi

Yamada

Uehara

et al. 2003

Journal of Biological Chemistry

126

158

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“…The GABA content of cells and medium was determined via enzymatic cycling for NADPH [19]. Fifty microlitre samples were incubated for 30 min, 37°C after addition of 80 ml GABA assay reagent (0.3 mol/l Tris-HCl buffer ± pH 8.9, 0.6 U/ml GABAse [Boehringer Mannheim] 5 mmol/l a-ketoglutarate, 0.01 % mercaptoethanol, 0.5 mmol/l NADP + ).…”

Section: Methodsmentioning

confidence: 99%

Nutrient regulation of gamma-aminobutyric acid release from islet beta cells

1997

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“…the genes encoding: neuronal cell adhesion molecule, N-cadherin [17], neuron specific enolase [18], glutamic acid and glutamate decarboxylase [19], and islet-brain 1 (IB1) and 2 (IB2) (c-Jun-NH 2 -terminal kinase interacting protein [JIP] 1 and 2 respectively) [20,21]. These characteristics probably originate from a common developmental lineage [22].…”

mentioning

confidence: 99%

JNK3 is abundant in insulin-secreting cells and protects against cytokine-induced apoptosis

et al. 2009

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Aims/hypothesis In insulin-secreting cells, activation of the c-Jun NH 2 -terminal kinase (JNK) pathway triggers apoptosis. Whereas JNK1 and JNK2 are ubiquitously produced, JNK3 has been described exclusively in neurons. This report aims to characterise the expression and role in apoptosis of the three JNK isoforms in insulin-secreting cells exposed to cytokines. Methods Sections of human and mouse pancreases were used for immunohistochemistry studies with isoformspecific anti-JNK antibodies. Human, pig, mouse and rat pancreatic islets were isolated by enzymatic digestion and RNA or protein extracts were prepared. RNA and protein levels were determined by quantitative RT-PCR and western blotting respectively, using JNK-isoform-specific primers and isoform-specific antibodies; activities of the three JNK isoforms were determined by kinase assays following quantitative immunoprecipitation/depletion of JNK3. JNK silencing was performed with small interfering RNAs and apoptotic rates were determined in INS-1E cells by scoring cells displaying pycnotic nuclei. Results JNK3 and JNK2 mRNAs are the predominant isoforms expressed in human pancreatic islets. JNK3 is nuclear while JNK2 is also cytoplasmic. In INS-1E cells, JNK3 knockdown increases c-Jun levels and caspase-3 cleavage and sensitises cells to cytokine-induced apoptosis; in contrast, JNK1 or JNK2 knockdown is protective. Conclusions/interpretation In insulin-secreting cells, JNK3 plays an active role in preserving pancreatic beta cell mass from cytokine attacks. The specific localisation of JNK3 in the nucleus, its recruitment by cytokines, and its effects on key transcription factors such as c-Jun, indicate that JNK3 is certainly an important player in the transcriptional control of genes expressed in insulin-secreting cells.

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High Concentration of GABA and High Glutamate Decarboxylase Activity in Rat Pancreatic Islets and Human Insulinoma

Cited by 231 publications

References 13 publications

Secretory Granule-mediated Co-secretion ofl-Glutamate and Glucagon Triggers Glutamatergic Signal Transmission in Islets of Langerhans

Secretory Granule-mediated Co-secretion ofl-Glutamate and Glucagon Triggers Glutamatergic Signal Transmission in Islets of Langerhans

Nutrient regulation of gamma-aminobutyric acid release from islet beta cells

JNK3 is abundant in insulin-secreting cells and protects against cytokine-induced apoptosis

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