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Glutamate Receptor Stimulation Up-Regulates Glutamate Uptake in Human Müller Glia Cells

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Abstract

Glutamate, the main excitatory amino acid in the vertebrate retina, is a well know activator of numerous signal transduction pathways, and has been critically involved in long-term synaptic changes acting through ionotropic and metabotropic glutamate receptors. However, recent findings underlining the importance of intensity and duration of glutamate stimuli for specific neuronal responses, including excitotoxicity, suggest a crucial role for Na+-dependent glutamate transporters, responsible for the removal of this neurotransmitter from the synaptic cleft, in the regulation of glutamate-induced signaling. Transporter proteins are expressed in neurons and glia cells, albeit most of glutamate uptake occurs in the glial compartment. Within the retina, Müller glia cells are in close proximity to glutamatergic synapses and participate in the recycling of glutamate through the glutamate/glutamine shuttle. In this context, we decided to investigate a plausible role of glutamate as a regulatory signal for its own transport in human retinal glia cells. To this end, we determined [3H]-D-aspartate uptake in cultures of spontaneously immortalized human Müller cells (MIO-M1) exposed to distinct glutamatergic ligands. A time and dose-dependent increase in the transporter activity was detected. This effect was dependent on the activation of the N-methyl D-aspartate subtype of glutamate receptors, due to a dual effect: an increase in affinity and an augmented expression of the transporter at the plasma membrane, as established via biotinylation experiments. Furthermore, a NMDA-dependent association of glutamate transporters with the cystoskeletal proteins ezrin and glial fibrillary acidic protein was also found. These results add a novel mediator of the glutamate transporter modulation and further strengthen the notion of the critical involvement of glia cells in synaptic function.

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Acknowledgments

Authors acknowledge Dr. G. Astrid Limb from the Institute of Ophthalmology, University College London for the generous donation of Müller Cell Line MIO-M1-cells. This work was supported by Grants IN200215 from PAPIIT/UNAM to AMLC and 79502 from Conacyt to A.O. O.M.F is supported by a Conacyt-Mexico fellowship. The technical assistance of Luis Cid and Luisa Clara Regina Hernandez-Kelly is acknowledged.

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Authors and Affiliations

  1. División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico, DF, Mexico

    Ana María López-Colomé & Edith López

  2. Laboratorio de Neurotoxicología, Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, 07360, Mexico, DF, Mexico

    Orquidia G. Mendez-Flores & Arturo Ortega

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  1. Ana María López-Colomé
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  2. Edith López
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  3. Orquidia G. Mendez-Flores
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  4. Arturo Ortega
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Correspondence to Arturo Ortega.

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López-Colomé, A.M., López, E., Mendez-Flores, O.G. et al. Glutamate Receptor Stimulation Up-Regulates Glutamate Uptake in Human Müller Glia Cells. Neurochem Res 41, 1797–1805 (2016). https://doi.org/10.1007/s11064-016-1895-z

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  • DOI: https://doi.org/10.1007/s11064-016-1895-z

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