Proteasomal degradation of the metabotropic glutamate receptor 1α is mediated by Homer-3 via the proteasomal S8 ATPase: Signal transduction and synaptic transmission

The metabotropic glutamate receptors (mGluRs) fine-tune the efficacy of synaptic transmission. This unique feature makes mGluRs potential targets for the treatment of various CNS disorders. There is ample evidence to show that the ubiquitin proteasome system mediates changes in synaptic strength leading to multiple forms of synaptic plasticity. The present study describes a novel interaction between post-synaptic adaptors, long Homer-3 proteins, and one of the 26S proteasome regulatory subunits, the S8 ATPase, that influences the degradation of the metabotropic glutamate receptor 1α (mGluR1α). We have shown that the two human long Homer-3 proteins specifically interact with human proteasomal S8 ATPase. We identified that mGluR1α and long Homer-3s immunoprecipitate with the 26S proteasome both in vitro and in vivo. We further found that the mGluR1α receptor can be ubiquitinated and degraded by the 26S proteasome and that Homer-3A facilitates this process. Furthermore, the siRNA mediated silencing of Homer-3 led to increased levels of total and plasma membrane-associated mGluR1α receptors. These results suggest that long Homer-3 proteins control the degradation of mGluR1α receptors by shuttling ubiquitinated mGluR-1α receptors to the 26S proteasome via the S8 ATPase which may modulate synaptic transmission. Miserable mortals who, like leaves, at one moment flame with life.and at another moment weakly perish (Homer, The Iliad). Synaptic complexity dictates that a sub-family of Homer proteins act as adaptors to deliver metabotropic glutamate receptors to neuronal 26S proteasomes for degradation. The present study was performed to identify new interactors with each of the non-redundant six ATPases in the base of the 19S regulator of the 26S proteasome to control the degradation of novel protein substrates. This study demonstrates that long Homer proteins act to deliver metabotropic glutamate receptor 1α to neuronal 26S proteasomes via the S8 ATPase for degradation. The findings serve to emphasise the importance of the ubiquitin proteasome system in controlling neuroreceptor activity in the nervous system.