Dendritic and axonal targeting of type 5 metabotropic glutamate receptor is regulated by Homer1 proteins and neuronal excitation

The physiological actions of neurotransmitter receptors are intimately link ed to their proper neuronal compartment localization. Here we studied the e ffect of the metabotropic glutamate receptor (mGluR)-interacting proteins, Homer1a, b, and c, in the targeting of mGluR5 in neurons. We found that mGl uR5 was exclusively localized in cell bodies when transfected alone in cult ured cerebellar granule cells. In contrast, mGluR5 was found also in dendri tes when coexpressed with Homer1b or Homer1c, and in both dendrites and axo ns when cotransfected with Homer1a. In dendrites, cotransfected mGluR5 and Homer1b/c formed clusters that colocalized with the synaptic marker synapto physin. Interestingly when transfected alone, the Homer proteins were also translocated to neurites but did not form such clusters. Depolarization of the neurons with a mixture of ionotropic glutamate receptor agonists, NMDA and kainate, or potassium channel blockers, tetraethylammonium and 4-aminop yridine, induced transient expression of endogenous Homer1a and persistent neuritic localization of transfected mGluR5 even long after degradation of Homer1a. These results suggest that Homer1a/b/c proteins are involved in th e targeting of mGluR5 to dendritic synaptic sites and/or axons and that thi s effect can be regulated by neuronal activity. Because the activity-depend ent effect of endogenous Homer1a was also long-lasting, the axonal targetin g of mGluR5 by this protein is likely to play an important role in synaptic plasticity.