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Glycine enhances microglial intracellular calcium signaling : a role for sodium-coupled neutral amino acid transporters

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Abstract
The inhibitory neurotransmitter glycine is known to enhance microglial nitric oxide production. However, up to now, the mechanism is undocumented. Since calcium is an important second messenger in both immune and glial cells, we studied the effects of glycine on intracellular calcium signaling. We found that millimolar concentrations of glycine enhance microglial intracellular calcium transients induced by 100 mu M ATP or by 500 nM thapsigargin. This modulation was unaffected by the glycine receptor antagonist strychnine and could not be mimicked by glycine receptor agonists such as taurine or beta-alanine, indicating glycine receptor independency. The modulation of calcium responses could be mimicked by several structurally related amino acids (e.g., serine, alanine, or glutamine) and was inhibited in the presence of the neutral amino acid transporter substrate alpha-aminoisobutyric acid (AIB). We correlated these findings to immunofluorescence glycine uptake experiments which showed a clear glycine uptake which was inhibited by AIB. Furthermore, all amino acids that were shown to modulate calcium responses also evoked AIB-sensitive inward currents, mainly carried by sodium, as demonstrated by patch clamp experiments. Based on these findings, we propose that sodium-coupled neutral amino acid transporters are responsible for the observed glycine modulation of intracellular calcium responses.
Keywords
Glycine, Calcium, Transporter, Microglia, Amino acid transport, GATED CHLORIDE CHANNEL, ENDOPLASMIC-RETICULUM, NITRIC-OXIDE, TNF-ALPHA, KAPPA-B, CELLS, ACTIVATION, MACROPHAGES, CULTURES, SERINE

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Chicago
Van den Eynden, Jimmy, Kristof Notelaers, Bert Brône, Daniel Janssen, Katherine Nelissen, Sheen SahebAli, Inge Smolders, Niels Hellings, Paul Steels, and Jean-Michel Rigo. 2011. “Glycine Enhances Microglial Intracellular Calcium Signaling : a Role for Sodium-coupled Neutral Amino Acid Transporters.” Pflugers Archiv-european Journal of Physiology 461 (4): 481–491.
APA
Van den Eynden, J., Notelaers, K., Brône, B., Janssen, D., Nelissen, K., SahebAli, S., Smolders, I., et al. (2011). Glycine enhances microglial intracellular calcium signaling : a role for sodium-coupled neutral amino acid transporters. PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 461(4), 481–491.
Vancouver
1.
Van den Eynden J, Notelaers K, Brône B, Janssen D, Nelissen K, SahebAli S, et al. Glycine enhances microglial intracellular calcium signaling : a role for sodium-coupled neutral amino acid transporters. PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY. 2011;461(4):481–91.
MLA
Van den Eynden, Jimmy et al. “Glycine Enhances Microglial Intracellular Calcium Signaling : a Role for Sodium-coupled Neutral Amino Acid Transporters.” PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 461.4 (2011): 481–491. Print.
@article{8604327,
  abstract     = {The inhibitory neurotransmitter glycine is known to enhance microglial nitric oxide production. However, up to now, the mechanism is undocumented. Since calcium is an important second messenger in both immune and glial cells, we studied the effects of glycine on intracellular calcium signaling. We found that millimolar concentrations of glycine enhance microglial intracellular calcium transients induced by 100 mu M ATP or by 500 nM thapsigargin. This modulation was unaffected by the glycine receptor antagonist strychnine and could not be mimicked by glycine receptor agonists such as taurine or beta-alanine, indicating glycine receptor independency. The modulation of calcium responses could be mimicked by several structurally related amino acids (e.g., serine, alanine, or glutamine) and was inhibited in the presence of the neutral amino acid transporter substrate alpha-aminoisobutyric acid (AIB). We correlated these findings to immunofluorescence glycine uptake experiments which showed a clear glycine uptake which was inhibited by AIB. Furthermore, all amino acids that were shown to modulate calcium responses also evoked AIB-sensitive inward currents, mainly carried by sodium, as demonstrated by patch clamp experiments. Based on these findings, we propose that sodium-coupled neutral amino acid transporters are responsible for the observed glycine modulation of intracellular calcium responses.},
  author       = {Van den Eynden, Jimmy and Notelaers, Kristof and Brône, Bert and Janssen, Daniel and Nelissen, Katherine and SahebAli, Sheen and Smolders, Inge and Hellings, Niels and Steels, Paul and Rigo, Jean-Michel},
  issn         = {0031-6768},
  journal      = {PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY},
  keywords     = {Glycine,Calcium,Transporter,Microglia,Amino acid transport,GATED CHLORIDE CHANNEL,ENDOPLASMIC-RETICULUM,NITRIC-OXIDE,TNF-ALPHA,KAPPA-B,CELLS,ACTIVATION,MACROPHAGES,CULTURES,SERINE},
  language     = {eng},
  number       = {4},
  pages        = {481--491},
  title        = {Glycine enhances microglial intracellular calcium signaling : a role for sodium-coupled neutral amino acid transporters},
  url          = {http://dx.doi.org/10.1007/s00424-011-0939-0},
  volume       = {461},
  year         = {2011},
}

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