The GluN3 subunit regulates ion selectivity within native N-methyl-d-aspartate receptors

Abstract

Highlights The GluN3 subunit is the least understood of all subunits that make up functional NMDARs in the brain. We show through ion substitution experiments that NMDARs containing GluN3 are more permeable to Ca 2+ than those containing just GluN1 and GluN2. We attribute these differences to their ability to screen for Ca 2+ over Na + . Subunit-dependent cation selectivity represents a hitherto unrealized mechanism for finer control of Ca 2+ influx enhancing the repertoire of synaptic NMDARs.

Synaptic Reshaping and Neuronal Outcomes in the Temporal Lobe Epilepsy

“…These receptors present the voltage-dependent block by extracellular Mg 2+ and high Ca 2+ permeability [ 62 ]. Moreover, unlike the AMPA receptor, NMDA receptors present slower activation and desensitization mechanisms, mainly due to the GluN2 subunit [ 56 ], while GluN3-containing receptors have reduced affinity for Mg 2+ and increased selective permeability for Ca 2+ over Na + , making them highly Ca 2+ permeable [ 63 ].…”

A Model for Predicting Cation Selectivity and Permeability in AMPA and NMDA Receptors Based on Receptor Subunit Composition

“…Dual regulation of monovalent and divalent cations in t -NMDARs is possible through ion selectivity ( Premkumar and Auerbach, 1996 ; Schneggenburger, 1998 ) alone, or in combination with pore-size/conductance-based screening of ions ( Burnashev et al, 1992 ; Wollmuth et al, 1996 ; Hille, 2001 ). Given the data from electrophysiological and/or ion-substitution experiments in the frontal, somatosensory and entorhinal cortices ( Pilli and Kumar, 2012 ; Beesley et al, 2020b ), together with the fact that unsolvated Na + and Ca 2+ ions are comparable in size ( Shannon, 1976 ), suggests that the increased permeability to Ca 2+ and decreased permeability to Na + in t -NMDARs arises primarily from GluN3-mediated cation selectivity. We next examine how this selectivity for and permeability to cations might come about.…”

“…The incorporation of GluN3A in the subunit composition of diheteromeric GluN1/GluN2B-containing NMDARs causes a ∼5 to 10-fold reduction in NMDA-evoked Na + current in oocytes (Sucher et al, 1995) which is consistent with what is also seen in t-NMDARs native to the brain (Pilli and Kumar, 2014;Beesley et al, 2020a,b). Together, these data suggest that without GluN3 control over selectivity of either monovalent (i.e., Na + ) or divalent (i.e., Ca 2+ ) cations (GluN3-containing d-NMDARs, however, appear to prefer Na + over Ca 2+ ) is diminished or lost and this situation is altered with the incorporation of GluN3 to make t-NMDARs, which acquire selectivity for Ca 2+ over Na + (Beesley et al, 2019(Beesley et al, , 2020b; Figure 2C3).…”

“…Thus, selectivity, referred to in this study as the ability of a receptor channel to screen extracellular ions (monovalent vs. divalent or cations vs. anions, for example), may be decoupled from permeability or the influx of ions from outside to inside of a cell through the channel, best exemplified by the NMDAR's voltage dependent Mg 2+ blockade. For these receptors at least, subunit dependent cation selectivity represents a departure from the commonly held belief that these glutamate-activated, voltage-dependent ionotropic channels are selective for both monovalent and divalent cations (Moriyoshi et al, 1991;Dingledine et al, 1999;Traynelis et al, 2010;Hansen et al, 2018;Beesley et al, 2020b). Lack of selectivity is, however, not the default state because ion channels are inherently selective for an ion species and single amino acid substitutions within their selectivity filters have been shown to drastically alter their ion-selective properties.…”

“…The model for cation selectivity and permeability discerned from these observations in NMDARs is validated by extending it to predict the behavior of AMPARs. Another overarching aim of this study is to address conflicting information in the literature regarding Ca 2+ permeability of GluN3-containing NMDARs from the fresh perspective of ion selectivity ( Perez-Otano et al, 2001 ; Chatterton et al, 2002 ; Matsuda et al, 2002 ; Pachernegg et al, 2012 ; Pilli and Kumar, 2012 ; Pankratov and Lalo, 2014 ; Otsu et al, 2019 ; Beesley et al, 2020b ).…”