Excitatory amino acid receptor activation produces a selective and long-lasting modulation of gene expression in hippocampal neurons.
Activation of excitatory amino acid (EAA) receptors in cultured hippocampal neurons causes down-regulation of the protein ligatin, a receptor for phosphoglycoproteins and a marker protein for membrane-vesicle transport systems. This reduction occurs at both physiologic and excitotoxic levels of glutamate stimulation and is accompanied by a significant decrease in steady state levels of ligatin mRNA. Reduction in ligatin mRNA occurs within 60 min and persists 24 h later. Steady state levels of mRNAs encoding cyclophilin, an ubiquitous cytosolic protein, and neuron specific-enolase (N-SE) are not diminished by glutamate receptor activation, demonstrating that down-regulation of ligatin mRNA was not a result of general catabolism. Further, this reduction in ligatin mRNA occurred without induction of HSP 70. Pharmacological studies using selective antagonists and agonists indicate that this down-regulation of ligatin gene expression is predominantly mediated by the N-methyl-D-aspartate (NMDA) subclass of EAA receptors and that Ca2+ is required. This is the first report that EAA receptor activation in hippocampal neurons can pretranslationally down-regulate gene expression in a rapid and long-lasting manner under physiologic, as well as cytotoxic conditions. The data support the hypothesis that modulation of neuronal gene expression may represent a molecular mechanism mediating some of the long-lasting functional and pathophysiological effects of EAA on cell function.
Jakoi
E R
ER
Department of Neurology, MCV Station, Richmond, VA 23298.
Sombati
S
S
Gerwin
C
C
DeLorenzo
R J
RJ
D000818:Animals; D001710:Biotin / Q000032:analysis; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000235:genetics; D015342:DNA Probes; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012313:RNA / Q000302:isolation & purification; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017459:Receptors, Amino Acid / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D015342:DNA Probes; D005971:Glutamates; D008565:Membrane Proteins; D012333:RNA, Messenger; D017459:Receptors, Amino Acid; C013090:ligatin; D018698:Glutamic Acid; D012313:RNA; D001710:Biotin; D004247:DNA