Metabotropic glutamate and GABAB receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells

Brice, Nicola; Váradi, Anikó; Ashcroft, S. J. H.; Molnár, Elek

doi:10.1007/s00125-001-0750-0

Cited by 132 publications

(116 citation statements)

References 44 publications

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“…In addition to their expression in the central nervous system, glutamate receptors have been reported to be widely expressed in peripheral, neuronal, or nonneuronal tissues, such as bone (7), skin (8), and pancreas (9). Indeed, recent studies have revealed that peripheral glutamate receptors may be involved in a variety of physiologic functions (20 -22).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, glutamate receptors have also been identified in peripheral nonneuronal tissues, including bone (7), skin (8), and pancreas (9); glutamate signaling has been implicated in differentiation of osteoblasts, proliferation of keratinocytes, and regulation of insulin secretion in these organs, respectively (7 -9). Moreover, glutamate and its receptors have been reported to play roles in development of melanoma in mice (10) and to promote growth of malignant glioma cells in vitro (11).…”

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confidence: 99%

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Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Chang

Yoo

Lim

et al. 2005

Clinical Cancer Research

114

109

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Purpose: Metabotropic glutamate receptors (mGluR) play a variety of roles in both neuronal and nonneuronal cells. Recently, we reported that mGluR4 mediates 5-fluorouracil resistance in a human colon cancer cell line. In this study, we evaluated the nonneural expression of mGluR4 and clarified the existence of mGluR4 in normal colon epithelium and colorectal carcinomas. We also investigated the association of mGluR4 expression levels with various clinicopathologic parameters. Experimental Design: mGluR4 expression was investigated in 21 normal and 312 malignant tissues from various organs using immunohistochemistry. In addition, 241 cases of colorectal carcinomas were examined and correlations between mGluR4 expression and various clinicopathologic parameters were then statistically analyzed. Results: Expression of mGluR4 was identified in the normal epithelia of the upper respiratory tract, gastrointestinal tracts, breast, uterine cervix, urinary bladder, and skin, whereas it was not detected in the thyroid, lung alveoli, liver, testis, or prostate. In the corresponding malignant tissues, mGluR4 expression was frequently identified in colorectal carcinoma (68%), followed by malignant melanoma, laryngeal carcinoma, and breast carcinomas. Expression of mGluR4 was detected in131 (54%) of 241colorectal carcinomas and12 (5%) cases among them showed overexpression in their cytoplasms. Loss of mGluR4 expression was negatively associated with tumor differentiation (P = 0.028), whereas overexpression of mGluR4 was positively associated with recurrence (P = 0.034) and poor disease-free survival (P = 0.017) in multivariate analyses. Conclusions: Our results suggest that mGluR4 signaling may play a role in colorectal carcinomas and that overexpression of mGluR4 is associated with poor prognosis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Chang

Yoo

Lim

et al. 2005

Clinical Cancer Research

114

109

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“…Another significant finding obtained in the present study is that the L-glutamate signaling triggers GABAergic response in clonal ␤ cells and isolated islets. The released L-glutamate may bind to the corresponding receptors on the islet cells, causing a paracrine or autocrine response (3)(4)(5)(6)(7)(8)(9)(10)(11). Islet ␤ cells contain GABA in SLMVs at concentrations comparable level to the central nervous systems (36,37).…”

Section: Discussionmentioning

confidence: 99%

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

121

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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“…This should enable those neurons to use lactate and ketone bodies as alternate energy substrates and act as regulators of glucosensing (8). Finally, whereas most ␤-cells are GABAergic (68), only half of the VMN GE neurons assessed expressed the mRNA for GAD, the GABA synthesizing enzyme (69). Thus, although many GE neurons may sense glucose similarly to ␤-cells, there are likely to be other populations of VMN GE and GI neurons that sense glucose through alternate pathways.…”

Section: Characterization Of Vmn Glucosensing Neuronsmentioning

confidence: 99%

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

et al. 2004

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To evaluate potential mechanisms for neuronal glucosensing, fura-2 Ca 2؉ imaging and single-cell RT-PCR were carried out in dissociated ventromedial hypothalamic nucleus (VMN) neurons. Glucose-excited (GE) neurons increased and glucose-inhibited (GI) neurons decreased intracellular Ca 2؉ ([Ca 2؉ ] i ) oscillations as glucose increased from 0.5 to 2.5 mmol/l. The Kir6.2 subunit mRNA of the ATP-sensitive K ؉ channel was expressed in 42% of GE and GI neurons, but only 15% of nonglucosensing (NG) neurons. Glucokinase (GK), the putative glucosensing gatekeeper, was expressed in 64% of GE, 43% of GI, but only 8% of NG neurons and the GK inhibitor alloxan altered [Ca 2؉ ] i oscillations in ϳ75% of GK-expressing GE and GI neurons. Insulin receptor and GLUT4 mRNAs were coexpressed in 75% of GE, 60% of GI, and 40% of NG neurons, although there were no statistically significant intergroup differences. Hexokinase-I, GLUT3, and lactate dehydrogenase-A and -B were ubiquitous, whereas GLUT2, monocarboxylate transporters-1 and -2, and leptin receptor and GAD mRNAs were expressed less frequently and without apparent relationship to glucosensing capacity. Thus, although GK may mediate glucosensing in up to 60% of VMN neurons, other regulatory mechanisms are likely to control glucosensing in the remaining ones. Diabetes 53:549 -559, 2004

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Metabotropic glutamate and GABAB receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells

Abstract: These data suggest that mGluRs and GABA(B)Rs play a role in the regulation of the endocrine pancreas with mechanisms probably involving direct activation or inhibition of voltage dependent Ca(2+)-channels, cAMP generation and G-protein-mediated modulation of K(ATP) channels.

Cited by 132 publications

References 44 publications

Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

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

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

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