Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1

Sengar, Ameet S.; Li, Hongbin; Zhang, Wenbo; Leung, Celeste; Saw, Ner Mu Nar; Wang, Yongqian; Tu, YuShan; Ross, P. Joel; Scherer, Stephen W.; Ellis, James; Brudno, Michael; Jia, Zhengping; Salter, Michael W.

doi:10.1016/j.celrep.2019.11.087

Cited by 36 publications

(51 citation statements)

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“…That synaptic NMDARs are normally composed of a mixture of N1-containing and N1-lacking GluN1 is consistent with findings comparing wild-type mice with genetically-modified mice either constitutively lacking Grin1 exon 5 (Grin1 5 termed GluN1a mice; Fig. 4A) or obligatorily expressing Grin1 exon 5 (Grin1 456 termed GluN1b mice) [14]. To investigate the role of the N1 cassette of GluN1 in glycine-primed depression of synaptic NMDARs at Schaffer collateral synapses onto pyramidal neurons we compared the effects of glycine conditioning on NMDAR EPSCs in GluN1a versus GluN1b mice.…”

Section: N1 Cassette Of Glun1 Prevents Glycine-primed Decline In Synasupporting

confidence: 87%

“…GluN1 splice variants are differentially expressed in various types of neurons, across different brain regions, and throughout distinct development stages [6][7][8][9]. N-terminal splicing affects NMDAR channel gating kinetics [10][11][12], as well as modulation by pH, Zn 2+ , extracellular polyamines [13] and long-term synaptic potentiation [14]. Many important properties of NMDA receptors such as glycine and glutamate potency, and voltage-dependent blockade by Mg 2+ are unaffected by the presence of N1 insert [4,5,15].…”

Section: Discussionmentioning

confidence: 99%

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Alternative splicing of GluN1 gates glycine-primed internalization of NMDA receptors

Rajani

Han

et al. 2020

Preprint

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SummaryN-methyl-D-aspartate receptors (NMDARs), a principal subtype of excitatory neurotransmitter receptor, are composed as tetrameric assemblies of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits. Gating of the NMDARs requires binding of four co-agonist molecules, but the receptors can signal non-ionotropically through binding of glycine, alone, to its cognate site on GluN1. A consequence of this signalling by glycine is that NMDARs are primed such that subsequent gating, produced by glycine and glutamate, drives receptor internalization. The GluN1 subunit is not a singular molecular species in the CNS, rather there are 8 alternatively spliced isoforms of this subunit produced by including or excluding the N1 and the C1, C2 or C2’ polypeptide cassettes. Whether alternative splicing affects glycine priming signalling is unknown. Here, using recombinant NMDARs expressed heterologously we discovered that glycine priming of NMDARs critically depends on alternative splicing: the four splice isoforms lacking the N1 cassette, encoded in exon 5, are primed by glycine whereas glycine priming is blocked in the four splice variants containing the N1 cassette. On the other hand, the C-terminal cassettes – C1, C2 or C2’ – had no effect on glycine priming signalling. Nor was glycine priming affected by the GluN2 subunit in the receptor. In wild-type mice we found that glycine primed internalization of synaptic NMDARs in CA1 hippocampal pyramidal neurons. With mice we engineered such that GluN1 obligatorily contained the N1 cassette, glycine did not prime synaptic NMDARs in pyramidal neurons. In contrast to pyramidal neurons, we discovered that in wild-type mice, synaptic NMDARs in CA1 inhibitory interneurons were resistant to glycine priming. But we recapitulated glycine priming in inhibitory interneurons in mice engineered such that GluN1 obligatorily lacked the N1 cassette. Our findings reveal a previously unsuspected molecular function for alternative splicing of GluN1 in controlling non-ionotropic signalling of NMDAR by glycine and the consequential cell surface dynamics of the receptors.

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Section: N1 Cassette Of Glun1 Prevents Glycine-primed Decline In Synasupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Alternative splicing of GluN1 gates glycine-primed internalization of NMDA receptors

Rajani

Han

et al. 2020

Preprint

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“…Moreover, NMDARs with GluN1 splice variants lacking the N1 cassette in the ATD, are primed by glycine whereas receptors containing the N1 cassette are not [48]. Both N1-containing and N1lacking NMDARs, however, gate normally upon coagonist stimulation [49]. Together these findings indicate that the molecular requirements within the extracellular region of GluN1 for glycine-induced priming differ from those for co-agonist gating.…”

Section: Outstanding Questionsmentioning

confidence: 99%

Tripartite signalling by NMDA receptors

2020

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N-methyl-D-aspartate receptors (NMDARs) are excitatory glutamatergic receptors that are fundamental for many neuronal processes, including synaptic plasticity. NMDARs are comprised of four subunits derived from heterogeneous subunit families, yielding a complex diversity in NMDAR form and function. The quadruply-liganded state of binding of two glutamate and two glycine molecules to the receptor drives channel gating, allowing for monovalent cation flux, Ca 2+ entry and the initiation of Ca 2+ -dependent signalling. In addition to this ionotropic function, non-ionotropic signalling can be initiated through the exclusive binding of glycine or of glutamate to the NMDAR. This binding may trigger a transmembrane conformational change of the receptor, inducing intracellular protein-protein signalling between the cytoplasmic domain and secondary messengers. In this review, we outline signalling cascades that can be activated by NMDARs and propose that the receptor transduces signalling through three parallel streams: (i) signalling via both glycine and glutamate binding, (ii) signalling via glycine binding, and (iii) signalling via glutamate binding. This variety in signal transduction mechanisms and downstream signalling cascades complements the widespread prevalence and rich diversity of NMDAR activity throughout the central nervous system and in disease pathology.

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“…Previous studies suggested that some cellular actions of gabapentin and pregabalin require activation of protein kinases (Gu and Huang, 2001;Maneuf and McKnight, 2001;Fehrenbacher et al, 2003), and it is clear that enhanced NMDA receptor function from phosphorylation contributes to neuropathic and chronic pain (Salter and Kalia, 2004;Salter and Pitcher, 2012). It has not yet been studied whether alternative splicing (Sengar et al, 2019) of NMDA receptors alters the interaction with 2-1 and modulation by gabapentinoid drugs.…”

Section: 2-1 Proteins Interact With Only Certain Nmda Receptorsmentioning

confidence: 99%

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

Taylor¹,

Harris²

2020

J Pharmacol Exp Ther

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The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, 2-1 or CaVa2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The 2-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that 2-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDAsensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to 2-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. Significance Statement It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the 2-1 protein. However, recent findings show that the 2-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.

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Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1

Cited by 36 publications

References 50 publications

Alternative splicing of GluN1 gates glycine-primed internalization of NMDA receptors

Alternative splicing of GluN1 gates glycine-primed internalization of NMDA receptors

Tripartite signalling by NMDA receptors

Analgesia with Gabapentin and Pregabalin May Involve N-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins

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