Retinoic acid mediates the expression of glutamate transporter-1 in rat astrocytes through genomic RXR action and non-genomic protein kinase C signaling pathway

• Published in: Journal of neurochemistry 2012-05, Vol.121 (4), p.537-550
• Main Authors: Chan, Ti-Ju, Her, Lu-Shiun, Liaw, Hung-Jiun, Chen, Mei-Chun, Tzeng, Shun-Fen
• Format: Article
• Language: English
• Subjects: Acids; Actins - metabolism; Animals; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; Bucladesine - pharmacology; Cell surface; Central nervous system; Cyclic AMP; dbcAMP; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Differentiation; DNA, Complementary - biosynthesis; DNA, Complementary - genetics; Down-Regulation - drug effects; Electrophoresis; Electrophoretic Mobility Shift Assay; Excitatory Amino Acid Transporter 1 - biosynthesis; Excitatory Amino Acid Transporter 1 - genetics; Forebrain; Fundamental and applied biological sciences. Psychology; Gene expression; Genomics; glutamate transporter-1; Glutamic Acid - metabolism; Heterozygote; Isolated neuron and nerve. Neuroglia; Lentivirus - genetics; Medical sciences; Motility; Neuroglia - metabolism; Neurology; Neurons - metabolism; Overexpression; Protein kinase C; Protein Kinase C - physiology; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Cell Surface - metabolism; Retinoic acid; Retinoic acid receptors; retinoid X receptor; Retinoid X receptors; Retinoid X Receptors - drug effects; Retinoid X Receptors - genetics; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Rodents; Signal transduction; Signal Transduction - drug effects; Transcription; Tretinoin - pharmacology; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2012.07715.x

J. Neurochem. (2012) 121, 537–550. Astrocytic glutamate transporter‐1 (GLT‐1) is responsible for 90% of forebrain glutamate uptake in the adult CNS. Retinoic acid (RA) is a potent regulator of neural cell differentiation and neuronal maturation in the developing CNS through activation of RA receptors/retinoic X receptors (RXRs) or non‐genomic mechanisms. Although rat GLT‐1 contains several RXR binding regions, RA‐triggered RXR mechanisms regulating GLT‐1 expression remain unknown. RA applied at submicromolar concentrations for 24 h significantly reduced GLT‐1 mRNA and membrane levels in astrocytes and dibutyryl cAMP (dbcAMP)‐primed astrocytes. An RXR agonist reduced astrocytic GLT‐1 mRNA expression, whereas an RXR antagonist blocked the effects of RA on the reduction of astrocytic GLT‐1 mRNA expression. Electrophoresis motility shift assay indicated that RA‐treatment increased astrocytic RXR‐DNA binding activity. RA‐induced reduction in GLT‐1 mRNA expression was also observed in dbcAMP‐primed astrocytes. Through lentivirus‐mediated astrocytic over‐expression of rat GLT‐1, levels of GLT‐1 in the processes of dbcAMP‐treated astrocytes were attenuated by exposure to RA. The protein kinase C inhibitor, Bis I, restored GLT‐1 distribution in the processes of RA‐treated dbcAMP‐primed astrocytes. These results suggest that RA reduces astrocytic GLT‐1 levels through both RXR‐mediated inhibition at the transcriptional level and triggering activation of protein kinase C which reduces cell surface GLT‐1 levels. RA‐induced genomic and nongenomic regulation of astrocytic GLT‐1 expressionThe study aimed to examine retinoic acid (RA)‐triggered mechanism for the regulation of glutamate transporter‐1 (GLT‐1) expression in astrocytes. We found that RA‐induced inhibition in GLT‐1 expression not only through retinoic X receptor (RXR) genomic action, but also through protein kinase C (PKC)‐induced non‐genomic mechanism. The findings suggest that endogenous RA signaling elicits a negative effect on astrocytic GLT‐1 expression during CNS development.