Abstract
BackgroundType B GABA receptors (GABA Rs) play a critical role in synaptic transmission. We carried out studies to determine whether neuronal cell surface expression of GABAB-Rs might be regulated by the Nogo receptor 1 (NgR1).ResultssiRNA knock-down of NgR1 resulted in a selective increase of GABAB R1 and GABAB R2 protein without altering the expression of GABAA receptor or GAD65. The increase in GABAB receptor subunits was unaccompanied by a change in mRNA, but inhibition of mTOR by rapamycin blocked the increase in GABAB protein. NgR1 siRNA also caused an increase in G protein coupled inwardly rectifying potassium channel (GIRK1). The increase in GABAB receptor and GIRK1 channel proteins was in the plasma membrane, determined by cell surface biotinylation. In NgR1 knockout mice, the amount of GABAB R2 and GIRK1 in hippocampus-derived synaptosomes was increased.ConclusionsTogether these findings suggest that NgR1 mediated modulation of synaptic transmission may be accomplished, at least in part, through modulation of G protein coupled receptors and channels.
Highlights
Type B Gamma aminobutyric acid (GABA) receptors (GABA Rs) play a critical role in synaptic transmission
Neurite outgrowth inhibitor A (NogoA) restricts synaptic plasticity in the adult hippocampus where NogoA neutralization, shRNA knockdown or deletion of NogoA induced changes in dendritic structure of pyramidal neurons and resulted in increases in long term potentiation [8,9]. These electrical and structural changes correlate with an increase in N-methyl-D-aspartic acid (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptor subunits and the scaffolding protein Postsynaptic density protein 95 (PSD95) that we previously found to occur in hippocampal neurons dendritic spines by mammalian target of rapamycin mediated activation following deletion of NogoA or Nogo receptor 1 (NgR1) [10]
Western blot analysis revealed that knock-down of NgR1 causes a significant increase in GABAB receptor subunits R1 and R2 protein compared to control Small interfering RNA (siRNA) treated cultures (Figure 1A)
Summary
Type B GABA receptors (GABA Rs) play a critical role in synaptic transmission. We carried out studies to determine whether neuronal cell surface expression of GABAB-Rs might be regulated by the Nogo receptor 1 (NgR1). NogoA restricts synaptic plasticity in the adult hippocampus where NogoA neutralization, shRNA knockdown or deletion of NogoA induced changes in dendritic structure of pyramidal neurons and resulted in increases in long term potentiation [8,9]. These electrical and structural changes correlate with an increase in NMDA and AMPA receptor subunits and the scaffolding protein PSD95 that we previously found to occur in hippocampal neurons dendritic spines by mammalian target of rapamycin (mTOR) mediated activation following deletion of NogoA or NgR1 [10]
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