Neto auxiliary proteins control both the trafficking and biophysical properties of the kainate receptor GluK1

Information is transmitted in the brain by cells called neurons. To communicate with neighboring cells, neurons release chemicals called neurotransmitters across a structure called a synapse that forms a junction between the cells. The neurotransmitters bind to receptors on the surface of the receiving neuron, and depending on the type of neurotransmitter released, make that neuron either more or less likely to signal to its neighbors. Excitatory neurotransmitters make neurons more likely to signal, and glutamate is the most common excitatory neurotransmitter in the brain. There are several different types of receptor that can bind to glutamate, one of which – the kainate receptor – is found at relatively few synapses. These synapses include some in the hippocampus, a region of the brain that is important for memory. Researchers have recently identified two auxiliary proteins, called Neto1 and Neto2, that interact with kainate receptors and appear to affect how strongly the kainate receptors respond when glutamate binds to them. However, the effect of the Neto proteins on one particular subunit of the kainate receptors – called GluK1 – had not been investigated in depth. CA1 pyramidal neurons are a group of neurons in the hippocampus that are able to produce kainate receptors, but these receptors are not found in CA1 pyramidal neuron synapses. Sheng et al. have now studied CA1 pyramidal neurons from rats, and found that these cells produce a limited amount of GluK1 on their surfaces. However, when GluK1 is expressed together with Neto1 or Neto2, GluK1 receptors appear on the cell surface. Through an independent mechanism Neto proteins also promote the targeting of surface GluK1 to the synapse. Unexpectedly, GluK1 was excluded from synapses that contain another type of glutamate receptor called AMPA receptors. By measuring the effect of Neto1 and Neto2 on the behavior of GluK1, Sheng et al. found that these proteins modified how the receptor responded to prolonged exposure to glutamate. Specifically, Neto1 increased how quickly GluK1 became desensitized to glutamate, while Neto2 decreased the rate of desensitization. This study demonstrates that Neto proteins play critical roles in controlling the location and biophysical properties of kainate receptors. It will be of interest to see how the present findings apply to other excitatory synapses in the brain.