Kainate receptors: on the dark side

Abstract

Synaptic glutamate receptors can be divided into metabotropic receptors, an eight-member GPCR family, and ionotropic glutamate receptors, a three-member family of NMDA, kainate, and AMPA tetrameric receptors. The most neglected are the five subunit (GluK1–5) kainate receptors, often either lumped with the AMPA receptors because of pharmacological ambiguity or relegated to the role of synaptic modulators (Lerma, 2003). In the paper by Lindstrom et al. (2014) published in this issue of The Journal of Physiology, not only is the kainate receptor shown to be central to synaptic communication, but subtypes of the receptor are localized to specific cell types in order to convey unique signals across the synapse. Nature demonstrates that receptor subtypes really matter and that neurons segregate proteins to multiplex information across labelled lines using binding and kinetics, not just hard wiring. The first synapse in retina is perhaps the ideal model for exploring the implications of receptor diversity. Photoreceptors release glutamate that is detected by three groups of cells. One, the On bipolar cell, uses the mGluR6 coupled with TRPM1 to invert the sign of the synapse – transforming photoreceptor excitation in the dark into a depolarizing On light response (Morgans et al. 2010). The other two, the horizontal cells and Off bipolar cells are sign conserving but use pharmacologically discrete ionotropic glutamate receptors. Thus three cell types perform different functions that are enabled by their specific and distinct glutamate receptors (Miller & Slaughter, 1986). The photoreceptor synapse is playing the game of telephone, sending out one message that is heard differently by each cell type. In the mouse retina, where at least 10 types of cone bipolar cells have been identified (Wassle et al. 2009; Helmstaedter et al. 2013), each of the majority middle wavelength sensitive cones contacts all of the bipolar cell types with only one exception (Haverkamp et al. 2005). But the diversity of postsynaptic receptors clearly means this divergence is not redundant. Bipolar cells, the interlocutors between the cone light sensors and the ganglion cell spike encoders, first establish parallel visual pathways. The DeVries lab has redefined this synapse. In a ground-breaking study, he found that the Off bipolar cells can be further subdivided and that each subtype expresses a different ionotropic receptor (DeVries, 2000). There are AMPA-expressing Off bipolar cells (termed cb2) that press their receptors very close to the cone release sites while other, kainate-expressing Off bipolar cells (termed cb1/cb3), are positioned at the base of the synaptic terminal far from release sites and consequently sense lower and more prolonged levels of glutamate (DeVries et al. 2006). But there are differences in the glutamate responses of the kainate receptor-expressing neurons that the current paper disentangles. The cb1 synapses are relatively simple, dominated by GluK1 receptors. The cb3 synapses appear more complex, probably GluK1/GluK5-containing heteromers and perhaps also containing GluK3. The receptors may also be modulated by Neto1. Furthermore, about 20% of the cb3 current derives from AMPA receptors. There may be further layers of complexity at the Off bipolar synapse. The cb1 kainate receptors have two distinct rates of recovery from desensitization, indicating either two desensitized states of the protein or modulation of the receptor to alter it recovery rate. In mouse retina the AMPA (type 1), kainate (type 2/3a), and mixed AMPA–kainate receptor (type 3b/4) Off bipolar cell types can also be distinguished, but do not match the homologous bipolar cells in guinea-pig (Puller et al. 2013). Either the homology classification needs revision or there is an intriguing flexibility in receptor expression. Furthermore, AMPA and kainate receptors in the mixed mouse bipolar cell do not co-localize, suggesting they can be differentially activated. Each new level of receptor complexity has revealed additional coding mechanisms and this is only the first retinal synapse.