Negative allosteric modulation of GluN1/GluN3 NMDA receptors

Abstract

NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission. Most native NMDA receptors are tetrameric assemblies of two glycine-binding GluN1 and two glutamate-binding GluN2 subunits. Co-assembly of the glycine-binding GluN1 with glycinebinding GluN3 subunits (GluN3A-B) creates glycine-activated receptors that possess strikingly different functional and pharmacological properties compared to GluN1/GluN2 NMDA receptors.

Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

“…The switch in subunit 2b–2a during development is crucial for proper maturation of the brain, as it is involved in neuronal function and synaptogenesis (Liu et al 2004 ; Luthi et al 2001 ). Interestingly, the expression of subunit grin2c was significantly increased after FR exposure and could be a sign of altered receptor affinity to the neurotransmitters (Yi et al 2020 ). It was previously observed that exposure to TMPP reduces the response to glutamate in mouse cortical neurons (Hausherr et al 2014 ).…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…NMDA receptors are obligate heterotetramers composed of two glycine-binding GluN1 subunits and either two identical glutamate-binding GluN2 subunits (i.e., diheteromeric receptors containing two types of subunits), or two different GluN2 subunits (i.e., triheteromeric receptors containing three types of subunits) (Monyer et al, 1992;Isacoff, 2007, 2008;Hansen et al, 2014;Karakas and Furukawa, 2014;Lee et al, 2014;. NMDA receptors composed of two GluN1 and two GluN3 subunits (GluN1/3), which do not bind glutamate, are expressed in neurons (Grand et al, 2018;Otsu et al, 2019;Zhu et al, 2020), and triheteromeric receptors composed of GluN1, GluN2, and GluN3 subunits (GluN1/GluN2/GluN3) might also exist [reviewed in Perez-Otano et al (2016), but see Ulbrich and Isacoff (2008)]. GluD1 and GluD2 subunits form homotetramers that serve as trans-synaptic adhesion complexes (i.e., synapse organizers) or require as yet Glutamate Receptor Ion Channels unidentified factors to form functional ion channels (Mayat et al, 1995;Zuo et al, 1997;Kohda et al, 2000;Naur et al, 2007;Elegheert et al, 2016;Burada et al, 2020b).…”

“…Thus, in contrast to GluN1/2 NMDA receptors (which require agonist occupancy of both GluN1 and GluN2 subunits), recombinant GluN1/3 receptors expressed in heterologous systems can open with agonist occupation of only the GluN3 subunit, whereas agonist binding to GluN1 produces strong desensitization (Awobuluyi et al, 2007;Madry et al, 2007;Kvist et al, 2013a;Grand et al, 2018). How this property influences GluN1/3 receptor function in the CNS, where ambient glycine should "predesensitize" the receptors (Grand et al, 2018;Otsu et al, 2019;Zhu et al, 2020) remains to be determined. Despite a lack of (Table 2 legend Kott et al (2007), 12 Schmitz et al (2017), 13 Twomey et al (2017b, 14 (Schwenk et al, 2009), 15 Gill et al (2012), 16 Klaassen et al (2016), 17 Kristensen et al (2011), GluA1 contains mutations S831A andS845A, 18 Tomita et al (2006), 19 Matt et al (2018), 20 Kato et al (2010), 21 Kato et al (2008), 22 Twomey et al (2016, some measures from tandem fusion protein of GluA2Q and cÀ2, 23 Khodosevich et al (2014) understanding of their activation mechanism, the description of glycine-activated currents in wild-type but not GluN3A KO neurons after block of glycine binding to GluN1 confirms neuronal expression of functional GluN1/3A receptors (Grand et al, 2018;Otsu et al, 2019;Zhu et al, 2020) (Section V. Glutamate Receptors in Neuronal Functions and Synaptic Plasticity).…”

“…An additional conductance level of 29-40 pS has been reported in patches excised from Xenopus oocytes or HEK cells expressing recombinant GluN1, GluN2A, and GluN3A (Das et al, 1998;Perez-Otano et al, 2001;Sasaki et al, 2002;Tong et al, 2008), although it is unclear whether this level arises from putative GluN1/2A/3A receptors or GluN1/3A receptors. Nonstationary variance analysis of glycine-activated native GluN1/3A receptors recorded in the presence of the competitive GluN1 antagonist CGP-78608 (to prevent predesensitization) suggested a weighted mean unitary conductance of 6 pS (assuming a reversal potential of 0 mV) (Zhu et al, 2020). There are no studies of the potential single-channel properties of wild-type GluD1 or GluD2 receptors, which do not show detectable channel opening in response to agonist binding.…”

Molecular Determinants of Spinal Hyperexcitability in Rat and Human Models of Pathological Pain

“…Further research is needed to elucidate the role played by GluN3containing NMDARs in pathological pain. Such future studies include the use of GluN3-specific antagonists such as EU1180-438 (Zhu et al, 2020), GluN3 enhancer CGP-78608 (Grand et al, 2018), and genetic knockdown models (Mohamad et al, 2013) in pain models. Because GluN3-NMDARs have been implicated in several known NMDAR-related pathologies, they are expressed in both the human and rodent spinal cord, and because they have a regulatory role in neuroplasticity, it is essential that their role in spinal nociceptive physiology be further explored.…”