Triheteromeric GluN1/GluN2A/GluN2C NMDARs with Unique Single-Channel Properties Are the Dominant Receptor Population in Cerebellar Granule Cells

Bhattacharya, Subhrajit; Khatri, Alpa; Swanger, Sharon A.; DiRaddo, John O.; Yi, Feng; Hansen, Kasper B.; Yuan, Hongjie; Traynelis, Stephen F.

doi:10.1016/j.neuron.2018.06.010

Cited by 51 publications

(44 citation statements)

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“…These dominant allosteric interactions by GluN2A are consistent with cryo-EM structures of GluN1/2A/2B and reduced inhibition by GluN2B-selective antagonists Stroebel et al 2014;Cheriyan et al 2016;Lü et al 2017). By contrast, GluN2A is not governing the function of GluN1/2A/2C receptors that display deactivation kinetics intermediate to those of GluN1/2A and GluN1/2C receptors (Bhattacharya et al 2018a). However, the GluN2C-selective positive allosteric modulators PYD-106 only potentiate diheteromeric GluN1/2C receptors, and not triheteromeric GluN1/2A/2C receptors (Khatri et al 2014;Bhattacharya et al 2018a;Kaiser et al 2018).…”

Section: Introductionsupporting

confidence: 73%

“…; Bhattacharya et al . ). However, as our understanding of the functional consequences of NMDA receptor subunit composition is evolving, more complex structure–function relationships are revealed that complicate quantitative determinations of contributions from native diheteromeric and triheteromeric NMDA receptor subtypes to synaptic transmission.…”

Section: Discussionmentioning

confidence: 97%

“…; Bhattacharya et al . ). Surprisingly, these studies revealed functional and pharmacological features of triheteromeric receptors that are not predicted from the average of the respective diheteromeric NMDA receptor properties.…”

Section: Introductionmentioning

confidence: 97%

“…By contrast, GluN2A is not governing the function of GluN1/2A/2C receptors that display deactivation kinetics intermediate to those of GluN1/2A and GluN1/2C receptors (Bhattacharya et al . ). However, the GluN2C‐selective positive allosteric modulators PYD‐106 only potentiate diheteromeric GluN1/2C receptors, and not triheteromeric GluN1/2A/2C receptors (Khatri et al .…”

Section: Introductionmentioning

confidence: 97%

“…GluN1/2A/2B, GluN1/2A/2C and GluN1/2B/2D), which contain two GluN1 and two different GluN2 subunits, are abundantly expressed in many neuronal populations (Sheng et al 1994;Takahashi et al 1996;Chazot & Stephenson, 1997;Luo et al 1997;Dunah et al 1998;Rumbaugh & Vicini, 1999;Cathala et al 2000;Piña-Crespo & Gibb, 2002;Brickley et al 2003;Jones & Gibb, 2005;Brothwell et al 2008;Gray et al 2011;Rauner & Köhr, 2011;Hildebrand et al 2014;Huang & Gibb, 2014;Swanger et al 2015;Perszyk et al 2016;Bhattacharya et al 2018a;Swanger et al 2018). Past studies of recombinant NMDA receptors almost exclusively focused on diheteromeric receptors but, recently, the properties of recombinant triheteromeric GluN1/2A/2B and GluN1/2A/2C receptors were described Stroebel et al 2014;Sun et al 2017;Bhattacharya et al 2018a). Surprisingly, these studies revealed functional and pharmacological features of triheteromeric receptors that are not predicted from the average of the respective diheteromeric NMDA receptor properties.…”

Section: Introductionmentioning

confidence: 99%

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Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors

Bhattacharya

Thompson

et al. 2019

The Journal of Physiology

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Key points Triheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS. Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+. GluN2B‐selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors. Abstract Triheteromeric NMDA‐type glutamate receptors that contain two GluN1 and two different GluN2 subunits contribute to excitatory neurotransmission in the adult CNS. In the present study, we report properties of the triheteromeric GluN1/2B/2D NMDA receptor subtype that is expressed in distinct neuronal populations throughout the CNS. We show that neither GluN2B, nor GluN2D dominate the functional properties of GluN1/2B/2D receptors because agonist potencies, open probability and the glutamate deactivation time course of GluN1/2B/2D receptors are intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. Furthermore, channel blockade of GluN1/2B/2D by extracellular Mg2+ is intermediate compared to GluN1/2B and GluN1/2D, although GluN1/2B/2D is more sensitive to blockade by ketamine and memantine compared to GluN1/2B in the presence of physiological Mg2+. Subunit‐selective allosteric modulators have distinct activity at GluN1/2B/2D receptors, including GluN2B‐selective antagonists, ifenprodil, EVT‐101 and CP‐101‐606, which inhibit with similar potencies but with different efficacies at GluN1/2B/2D (∼65% inhibition) compared to GluN1/2B (∼95% inhibition). Furthermore, the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. We show that these key features of allosteric modulation of recombinant GluN1/2B/2D receptors are also observed for NMDA receptors in hippocampal interneurons but not CA1 pyramidal cells, which is consistent with the expression of GluN1/2B/2D receptors in interneurons and GluN1/2A/2B receptors in pyramidal cells. Altogether, we uncover previously unknown functional and pharmacological properties of triheteromeric GluN1/2B/2D receptors that can facilitate advances in our understanding of their physiological roles in neural circuit function and therapeutic drug actions.

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Section: Introductionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors

Bhattacharya

Thompson

et al. 2019

The Journal of Physiology

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NMDA Receptors

Gibb¹

2019

Encyclopedia of Life Sciences

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N‐methyl‐D‐aspartate (NMDA) receptors are one type of glutamate receptor. They play key roles in synaptic transmission and plasticity in the central nervous system. They are uniquely activated by simultaneous binding of the amino acids glycine and l ‐glutamate. These receptors are proteins that form an ion channel across the cell membrane, commonly formed by assembly of two glutamate‐binding GluN2 subunits and two glycine‐binding GluN1 subunits. The ion channel opens following receptor activation, allowing Na + and Ca 2+ ions to cross the cell membrane, thus translating the transient chemical signal provided by release of glutamate from a presynaptic neuron, into postsynaptic electrical and biochemical Ca 2+ signals. Crucially, the characteristics of NMDA receptor signalling depend on the receptor subunit composition, particularly the nature of the GluN2 subunits which can be of four different types, creating unique and important variations in properties that provide a rich diversity of NMDA receptor signalling in the brain. Key Concepts NMDA receptor functional diversity is determined by the receptor subunit composition. Key functional attributes of NMDA receptors are the Ca 2+ permeability and Mg 2+ block of the transmembrane ion channel and the slow kinetics of receptor activation which can last for hundreds of milliseconds. The receptor subunits are somewhat modular in nature with key functional attributes depending on particular domains of the subunit protein. Domain interactions are an emerging concept in understanding NMDA receptor structure–function relationships. Allosteric modulators of NMDA receptors can both enhance or inhibit receptor function and provide the future possibility of novel therapeutic approaches to diseases of the nervous system associated with altered NMDA receptor function.

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GluN2A‐Selective NMDA Receptor Antagonists: Mimicking the U‐Shaped Bioactive Conformation of TCN‐201 by a [2.2]Paracyclophane System

et al. 2022

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Under physiological conditions, N‐Methyl‐D‐Aspartate (NMDA) receptors play a crucial role for synaptic plasticity, long‐term potentiation and long‐term depression. However, overactivation of NMDA receptors can result in excitotoxicity, which is associated with various neurological and neurodegenerative diseases. The physiological properties of NMDA receptors are strongly dependent on the GluN2 subunit incorporated into the heterotetrameric NMDA receptor. Therefore, subtype selective NMDA receptor modulators are of high interest. Since prototypical GluN2A‐NMDA receptor antagonists TCN‐201 and its MPX‐analogs adopt a U‐shaped conformation within the binding pocket, paracyclophanes were designed containing the phenyl rings in an already parallel orientation. Docking studies of the designed paracyclophanes show a similar binding pose as TCN‐201. [2.2]Paracyclophanes with a benzoate or benzamide side chain were prepared in four‐step synthesis, respectively, starting with a radical bromination in benzylic 1‐position of [2.2]paracyclophane. In two‐electrode voltage clamp experiments using Xenopus laevis oocytes transfected with cRNAs for the GluN1‐4a and GluN2A subunits, the esters and amides (conc. 10 μM) did not show considerable inhibition of ion flux. It can be concluded that the GluN2A‐NMDA receptor does not accept ligands with a paracyclophane scaffold functionalized in benzylic 1‐position, although docking studies had revealed promising binding poses for benzoic acid esters and benzamides.

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Triheteromeric GluN1/GluN2A/GluN2C NMDARs with Unique Single-Channel Properties Are the Dominant Receptor Population in Cerebellar Granule Cells

Cited by 51 publications

References 100 publications

Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors

Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors

NMDA Receptors

GluN2A‐Selective NMDA Receptor Antagonists: Mimicking the U‐Shaped Bioactive Conformation of TCN‐201 by a [2.2]Paracyclophane System

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