Homer is a crucial postsynaptic scaffolding protein involved in both maintenance and activity-induced plasticity of the synapse. However, its quaternary structure has yet to be determined. We conducted a series of biophysical experiments that provide the first evidence that Homer forms a tetramer via its coiled-coil domain, in which all subunits are aligned in parallel orientation. To test the importance of the tetrameric structure for functionality, we engineered dimeric and tetrameric Homer by deleting a part of coiled-coil domain or replacing it with artificially engineered dimeric or tetrameric coiled-coil domain from a yeast protein. The structure–activity relationship was determined by assaying cocluster formation with its ligand in heterologous cells, distribution in dendritic spines, and turnover rate of protein exist in dendritic spines. Our results provide the first insight into the structure of native Homer protein as a tetramer and the functional significance conferred by that structure.

Many kinds of transporters contribute to glutamatergic excitatory synaptic transmission. Glutamate is loaded into synaptic vesicles by vesicular glutamate transporters to be released from presynaptic terminals. After synaptic vesicle release, glutamate is taken up by neurons or astrocytes to terminate the signal and to prepare for the next signal. Glutamate transporters on the plasma membrane are responsible for transporting glutamate from extracellular fluid to cytoplasm. Glutamate taken up by astrocyte is converted to glutamine by glutamine synthetase and transported back to neurons through glutamine transporters on the plasma membranes of the astrocytes and then on neurons. Glutamine is converted back to glutamate by glutaminase in the neuronal cytoplasm and then loaded into synaptic vesicles again. Here, the structures of glutamate transporters and glutamine transporters, their conformational changes, and how they use electrochemical gradients of various ions for substrate transport are summarized. Pharmacological regulations of these transporters are also discussed.