8.A.47 The Neuropilin and Tolloid-like (Neto) Family 

Kainate receptors are a family of ionotropic glutamate receptors whose physiological roles differ from those of other subtypes of glutamate receptors in that they predominantly serve as modulators, rather than mediators, of synaptic transmission (Copits and Swanson 2012). Neuronal kainate receptors exhibit unusually slow kinetic properties that have been difficult to reconcile with the behaviour of recombinant kainate receptors. However, the neuropilin and tolloid-like 1 (NETO1) and NETO2 proteins are auxiliary kainate receptor subunits that shape both the biophysical properties and synaptic localization of these receptors (Howe 2014). Several members of this family are large (700 - 900 aas; ~ twice as large as the monodomain proteins), and they contain at least two domains, an N-terminal domain belonging to TC family 8.A.47, and a fused domain belonging to TC family 8.A.154.  In view of this fact, it can be surmised that the members of these two families may function together.

Neto2 also interacts with the neuron-specific K⁺-Cl^- cotransporter (KCC2) in the central nervous system (CNS). Efficient KCC2 transport is essential for setting the neuronal Cl^- gradient, which is required for fast GABAergic inhibition. Neto2 is required to maintain the normal abundance of KCC2 in neurons, and increases KCC2 function by binding to the active oligomeric form of this cotransporter (Mahadevan et al. 2015). The amino-terminal domains of GluK1 and GluK2 control the strikingly different trafficking properties between these two receptors and are critical for synaptic expression of heteromeric receptors at mossy fiber-CA3 synapses. They also mediate the differential dependence on Neto proteins for surface and synaptic trafficking of GluK1 and GluK2 (Sheng et al. 2017) and regulate interneuronal somatodendritic and presynaptic kainate receptors to control network inhibition (Wyeth et al. 2017).

Kainate receptor heteromerization with the auxiliary subunits, Neto1 and Neto2, attenuate polyamine ion-channel block by facilitating polyamine permeation (Brown et al. 2016). Relief of polyamine block in GluK2/GluK5 heteromers results from a key proline residue that produces architectural changes in the channel pore α-helical region. The neto auxiliary subunits exert an additive effect to heteromerization, and thus relieve the polyamine block.