Glutamate Regulates Intracellular Calcium and Gene Expression in Oligodendrocyte Progenitors through the Activation of DL-α-Amino-3- Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 8; pp. 3215 - 3219
• Main Authors: PENDE, M, HOLTZCLAW, L. A, CURTIS, J. L, RUSSELL, J. T, GALLO, V
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 12.04.1994; National Acad Sciences
• Subjects: Agonists; Animals; Biological and medical sciences; Calcium - metabolism; DNA-Binding Proteins - genetics; Early Growth Response Protein 1; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Genes, fos; Genes, Immediate-Early; Genes, jun; Glutamate receptors; Glutamates - pharmacology; Immediate-Early Proteins; Isolated neuron and nerve. Neuroglia; Messenger RNA; Neural stem cells; Neurons; Oligodendroglia; Oligodendroglia - cytology; Potassium - physiology; Progenitor cells; Rats; Rats, Sprague-Dawley; Receptors; Receptors, AMPA - physiology; Receptors, Kainic Acid - physiology; RNA; RNA, Messenger - genetics; Stem cells; Transcription Factors - genetics; Vertebrates: nervous system and sense organs; Glial cell; Calcium; Rat; Rodentia; Neuroglía; Glutamate receptor; Cell differentiation; Gene expression; Glutamate; Precursor; Vertebrata; AMPA receptor; Regulation(control); Cell line; Mammalia; Oligodendrocyte; Intracellular; Immediate early gene
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.8.3215

Oligodendrocytes and their progenitors (O-2A) express functional kainate- and DL-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptors. The physiological consequences of activation of these receptors were studied in purified rat cortical O-2A progenitors and in the primary oligodendrocyte cell line CG-4. Changes in the mRNA levels of a set of immediate early genes were studied and were correlated to intracellular Ca2+concentration, as measured by fura-2 Ca2+imaging. Both in CG-4 and in cortical O-2A progenitors, basal mRNA levels of NGFI-A were much higher than c-fos, c-jun, or jun-b. Glutamate, kainate, and AMPA greatly increased NGFI-A mRNA and protein by activation of membrane receptors in a Ca2+-dependent fashion. Agonists at non-N-methyl-D-aspartate receptors promoted transmembrane Ca2+influx through voltage-dependent channels as well as kainate and/or AMPA channels. The influx of Ca2+ions occurring through glutamate-gated channels was sufficient by itself to increase the expression of NGFI-A mRNA. AMPA receptors were found to be directly involved in intracellular Ca2+and NGFI-A mRNA regulation, because the effects of kainate were greatly enhanced by cyclothiazide, an allosteric modulator that selectively suppresses desensitization of AMPA but not kainate receptors. Our results indicate that glutamate acting at AMPA receptors regulates immediate early gene expression in cells of the oligodendrocyte lineage by increasing intracellular calcium. Consequently, modulation of these receptor channels may have immediate effects at the genomic level and regulate oligodendrocyte development at critical stages.