GABAAergic stimulation modulates intracellular protein arginine methylation

NEUROSCIENCE LETTERS

卷:572

Article

Denman, Robert B.¹  Xie, Wen²  Merz, George³  Sung, Ying-Ju⁴ 

[1] New York State Inst Basic Res Dev Disabil, Dept Mol Biol, New York, NY 10314 USA

[2] Cornell Univ, Weill Med Coll, Dept Med, Div Hematol & Med Oncol, New York, NY 10021 USA

[3] New York State Inst Basic Res Dev Disabil, Dept Dev Neurobiol, New York, NY 10314 USA

[4] Commonwealth Med Coll, Dept Basic Sci, Scranton, PA 18509 USA

关键词: Protein arginine methylation;    GABA(A) receptor;    Fragile X syndrome;    Fmr1 knockout mice;   

DOI  :  10.1016/j.neulet.2014.04.036

来源: Elsevier

【 摘 要 】

Changes in cytoplasmic pH are known to regulate diverse cellular processes and influence neuronal activities. In neurons, the intracellular alkalization is shown to occur after stimulating several channels and receptors. For example, it has previously demonstrated in P19 neurons that a sustained intracellular alkalinization can be mediated by the Na+/H+ antiporter. In addition, the benzodiazepine binding subtypes of the gamma-amino butyric acid type A (GABA(A)) receptor mediate a transient intracellular alkalinization when they are stimulated. Because the activities of many enzymes are sensitive to pH shift, here we investigate the effects of intracellular pH modulation resulted from stimulating GABA(A) receptor on the protein arginine methyltransferases (PRMT) activities. We show that the major benzodiazepine subtype (2 alpha(1), 2 beta(2), 1 gamma(2)) is constitutively expressed in both undifferentiated P19 cells and retinoic acid (RA) differentiated P19 neurons. Furthermore stimulation with diazepam and, diazepam plus muscimol produce an intracellular alkalinization that can be detected ex vivo with the fluorescence dye. The alkalinization results in significant perturbation in protein arginine methylation activity as measured in methylation assays with specific protein substrates. Altered protein arginine methylation is also observed when cells are treated with the GABAA agonist muscimol but not an antagonist, bicuculline. These data suggest that pH-dependent and pH-independent methylation pathways can be activated by GABA(A)ergic stimulation, which we verified using hippocampal slice preparations from a mouse model of fragile X syndrome. (C) 2014 The Authors. Published by Elsevier Ireland Ltd.

【 授权许可】

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