Molecular evidence for a glycine-gated chloride channel in macrophages and leukocytes

Froh, Matthias; Thurman, Ronald G.; Wheeler, Michael D.

doi:10.1152/ajpgi.00503.2001

Cited by 102 publications

(112 citation statements)

References 34 publications

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“…However, 0.5, 1, and 2 mmol/L GLY significantly attenuated 100 µg/mL LPS-induced TNFα release from the cardiomyocytes ( Figure 1B). [17] , and GLY stimulates the GLY-gated chloride channel, resulting in chloride influx and hyperpolarization of the membrane, which in turn blunts the increase in [Ca 2+ ] c in leukocytes [5] . Thus, it is necessary to examine the effect of GLY on Ca 2+ influx in cardiomyocytes.…”

Section: Resultsmentioning

confidence: 99%

“…It is possible that LPS at concentrations less than 10 µg/mL induces an increase in [Ca 2+ ] c mainly via intracellular calcium release. A previous study suggested that GLY inhibited calcium influx mainly from the extracellular space [5] . Therefore, the inhibitory amplitude of 2 mmol/L GLY on [Ca 2+ ] c elevation in cardiomyocytes exposed to 1 and 10 µg/mL LPS is not enough to inhibit TNFα production.…”

Section: Discussionmentioning

confidence: 97%

“…These results suggest that GLY may block calcium influx from the extracellular space and inhibit the potassium chloride-or LPS-induced increase in [Ca 2+ ] c in cardiomyocytes via the GLY receptor. It is known that the GLY receptor is a ligand-gated chloride channel [5] . In order to further confirm the presence of GLY-gated chloride channels in cardiomyocytes, potassium chloride was replaced with dipotassium hydrogen phosphate to minimize the chloride concentration in the extracellular space.…”

Section: Discussionmentioning

confidence: 99%

“…Dietary GLY can improve rat survival in endotoxin shock and significantly reduce the lipopolysaccharide (LPS)-induced elevation in serum tumor necrosis factor-α (TNFα) levels, hepatic necrosis and lung injury [4] . Furthermore, Froh et al demonstrated that macrophages and leukocytes expressed a GLY-gated chloride channel with molecular and pharmacological properties similar to those of the GLY receptor in the central nervous system [5] . GLY stimulates the GLY-gated chloride channel, resulting in chloride influx and hyperpolarization of the membrane, which prevents Kupffer cell activation and consequently blunts the increase in cytosolic calcium concentration ([Ca 2+ ] c) and in TNFα production in response to LPS [5,6] .…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Froh et al demonstrated that macrophages and leukocytes expressed a GLY-gated chloride channel with molecular and pharmacological properties similar to those of the GLY receptor in the central nervous system [5] . GLY stimulates the GLY-gated chloride channel, resulting in chloride influx and hyperpolarization of the membrane, which prevents Kupffer cell activation and consequently blunts the increase in cytosolic calcium concentration ([Ca 2+ ] c) and in TNFα production in response to LPS [5,6] . Most recently, we found positive immunohistochemical staining for the GLY receptor in the rat heart [7] , and we also demonstrated that GLY markedly improved the monophasic action potential in the isolated rat heart exposed to LPS and reduced LPS-induced myocardial injury [8] .…”

Section: Introductionmentioning

confidence: 99%

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Glycine inhibits the LPS-induced increase in cytosolic Ca2+ concentration and TNFα production in cardiomyocytes by activating a glycine receptor

Wang

et al. 2009

Acta Pharmacol Sin

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Aim: Previous studies have demonstrated that glycine (GLY) markedly reduces lipopolysaccharide (LPS)-induced myocardial injury. However, the mechanism of this effect is still unclear. The present study investigated the effect of GLY on cytosolic calcium concentration ([Ca 2+ ] c ) and tumor necrosis factor-α (TNFα) production in cardiomyocytes exposed to LPS, as well as whether the glycine-gated chloride channel is involved in this process. Methods: Neonatal rat cardiomyocytes were isolated, and the [Ca 2+ ] c and TNFα levels were determined by using Fura-2 and a Quantikine enzyme-linked immunosorbent assay, respectively. The distribution of the GLY receptor and GLY-induced currents in cardiomyocytes were also investigated using immunocytochemistry and the whole-cell patch-clamp technique, respectively. Results: LPS at concentrations ranging from 10 ng/mL to 100 µg/mL significantly stimulated TNFα production. GLY did not inhibit TNFα production induced by LPS at concentrations below 10 ng/mL but did significantly decrease TNFα release stimulated by 100 µg/mL LPS and prevented an LPS-induced increase in [Ca 2+ ] c , which was reversed by strychnine, a glycine receptor antagonist. GLY did not block the isoproterenol-induced increase in [Ca 2+ ] c , but did prevent the potassium chloride-induced increase in [Ca 2+ ] c in cardiomyocytes. Strychnine reversed the inhibition of the KCl-stimulated elevation in [Ca 2+ ] c by GLY. In chloride-free buffer, GLY had no effect on the dipotassium hydrogen phosphate-induced increase in [Ca 2+ ] c . Furthermore, GLY receptor α 1 and β subunit-immunoreactive spots were observed in cardiomyocytes, and GLY-evoked currents were blocked by strychnine. Conclusion: Cardiomyocytes possess the glycine-gated chloride channel, through which GLY prevents the increase in [Ca 2+ ] c and inhibits the TNFα production induced by LPS at high doses in neonatal rat cardiomyocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Glycine inhibits the LPS-induced increase in cytosolic Ca2+ concentration and TNFα production in cardiomyocytes by activating a glycine receptor

Wang

et al. 2009

Acta Pharmacol Sin

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Glycine Receptors

Breitinger

2014

Encyclopedia of Life Sciences

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Absract The inhibitory glycine receptor is a ligand‐gated chloride channel of the cys‐loop receptor family. As a chloride‐selective channel, it mediates rapid synaptic inhibition in mammalian spinal cord, brainstem, higher brain centres and nonneuronal tissues. In recent years, our understanding of glycine receptors has steadily grown, adding considerable depth to our knowledge of receptor function, structure, cellular trafficking and tissue distribution. Furthermore, new roles for glycinergic transmission in higher brain function have been uncovered. Glycine receptors should no longer be considered only as mediators of spinal reflexes, but were also found to play an important role in the modulation of higher brain function, including vision, hearing and pain signalling. The identification of novel agonists and modulators underlines the relevance of the inhibitory glycine receptor as a therapeutic target. This review extends a previous article of this series and highlights key developments in glycine receptor research over the past 2–3 years. Key Concepts: Glycine receptors are key mediators of rapid synaptic inhibition in mammalian spinal cord and higher brain centres. Glycine receptors are members of the cys‐loop family of ligand‐gated ion channel receptors. Glycinergic signalling is involved in motor control, pain signalling, vision, hearing and other brain functions. Mutations in glycine receptor genes underlie human hyperekplexia and related myoclonic diseases. New modulators of glycine receptor function are rare and of considerable medicinal interest.

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The inhibitory neurotransmitter glycine modulates macrophage activity by activation of neutral amino acid transporters

Carmans

Hendriks

Thewissen

et al. 2010

J of Neuroscience Research

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Glycine, an important inhibitory neurotransmitter in the mammalian central nervous system (CNS), has been shown to modulate peripheral immune cell responses. In that respect, glycine levels are increased in several neuroinflammatory disorders, like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, we show that glycine modulates macrophage effector functions implicated in CNS inflammation and in other related inflammatory conditions. We demonstrate that glycine does not affect the production of reactive oxygen species, but stimulates myelin phagocytosis and the production of the pro-inflammatory mediators nitric oxide (NO) and tumor necrosis factor (TNF)-α by rat macrophages. These effects of glycine are not mediated by the glycine receptor (GlyR) or by glycine transporters (GlyTs), since neither the GlyR antagonist strychnine, nor the antagonist of GlyT1 (ALX5407) reverse the observed effects. In contrast, 2-aminoisobutyric acid, a substrate of neutral amino acid transporters (NAATs), inhibits the glycine-mediated enhancement of myelin phagocytosis as well as of NO and TNF-α production. In conclusion, our findings demonstrate that glycine modulates macrophage function through activation of NAATs. Glycine may thereby influence immunological processes in inflammatory diseases involving macrophage activation and demyelination, including MS, and related conditions associated with altered glycine levels.

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Molecular evidence for a glycine-gated chloride channel in macrophages and leukocytes

Cited by 102 publications

References 34 publications

Glycine inhibits the LPS-induced increase in cytosolic Ca2+ concentration and TNFα production in cardiomyocytes by activating a glycine receptor

Glycine inhibits the LPS-induced increase in cytosolic Ca2+ concentration and TNFα production in cardiomyocytes by activating a glycine receptor

Glycine Receptors

The inhibitory neurotransmitter glycine modulates macrophage activity by activation of neutral amino acid transporters

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