A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors

Mullasseril, Praseeda; Hansen, Kasper B.; Vance, Katie M.; Ogden, Kevin K.; Yuan, Hongjie; Kurtkaya, Natalie L.; Santangelo, Rose M; Orr, Anna G.; Le, Phuong; Vellano, Kimberly; Liotta, Dennis; Traynelis, Stephen F.

doi:10.1038/ncomms1085

Cited by 143 publications

(191 citation statements)

References 41 publications

(36 reference statements)

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“…Previous work identified two distinct regions of GluN1/GluN2D that were critical for potentiation by CIQ and analogs: the ATD-ABD linker and the first transmembrane helix, M1 (Mullasseril et al, 2010). These regions are seemingly independent of each other based on homology to the GluA2 tetrameric crystal structure, with the ATD-ABD linker being about 65-70 Å extracellular to the M1 helix (Sobolevsky et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…These compounds show varying subunit-selectivity and structural determinants of action. Additionally, the first class of positive allosteric modulators selective for GluN2C-and GluN2D-containing NMDA receptors was recently reported (Mullasseril et al, 2010). This class of potentiators doubles the current response to maximally effective concentrations of agonist for NMDA receptors containing GluN2C or GluN2D.…”

Section: Orgmentioning

confidence: 99%

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Contribution of the M1 Transmembrane Helix and Pre-M1 Region to Positive Allosteric Modulation and Gating of N-Methyl-d-Aspartate Receptors

Ogden

Traynelis

2013

Mol Pharmacol

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N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels whose function is critical for normal excitatory synaptic transmission in the brain and whose dysfunction has been implicated in several neurologic conditions. NMDA receptor function is subject to extensive allosteric regulation both by endogenous compounds and by exogenous small molecules. Elucidating the structural determinants and mechanism of action by which allosteric regulators control gating will enhance our understanding of NMDA receptor activation and facilitate the development of novel therapeutics. Here, we investigated the structural determinants for (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), a GluN2C/ 2D-selective positive allosteric modulator. We show that CIQ does not bind to the amino-terminal domain of the NMDA receptor and does not share structural determinants with modulators acting at the agonist-binding domain dimer interface or ion channel pore. Rather, we identified critical determinants of CIQ modulation in the region near the first transmembrane helix of GluN2D, including in a putative pre-M1 cuff helix that may influence channel gating. We also show that mutations within the GluN2D pre-M1 region alter open probability of the NMDA receptor. These results suggest a novel site of action for potentiation of NMDA receptors by small molecules and implicate the pre-M1 region in NMDA receptor gating.

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Section: Resultsmentioning

confidence: 99%

Section: Orgmentioning

confidence: 99%

Contribution of the M1 Transmembrane Helix and Pre-M1 Region to Positive Allosteric Modulation and Gating of N-Methyl-d-Aspartate Receptors

Ogden

Traynelis

2013

Mol Pharmacol

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“…Moreover, since ionotropic glutamate receptors also play a key role in regulating the strength of corticostriatal excitatory synapses, their abnormal activation might be also involved in the alteration of neuronal firing patterns in certain regions of the basal ganglia and significantly contribute to the motor symptoms associated with PD (Wenthold et al, 1996;Hallett and Standaert, 2004;Mullasseril et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation

et al. 2012

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Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of ␣-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus.Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposuretoa-synoligomersdrivestheincreaseofglutamatergicsynaptictransmission,preventingfurtherpotentiationbyphysiologicalstimuli.Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.

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“…NMDAR activity is under the control of complex modulations (12,13). In particular, NMDARs possess two main regulatory binding domains that are referred to as the glutamate and the coagonist glycine sites, respectively (13).…”

Section: Significancementioning

confidence: 99%

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Yang

Ruchti

Petit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

404

373

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L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.brain energy metabolism | learning and memory | astrocyte-neuron interaction | astrocyte-neuron lactate shuttle T he transfer of L-lactate from astrocytes to neurons was recently shown to be necessary for the establishment of longterm memory (LTM) in an inhibitory avoidance (IA) paradigm and for the maintenance of in vivo long-term potentiation (LTP) in the rodent hippocampus (1). This key role of L-lactate in neuronal plasticity mechanisms was demonstrated in experiments in which specific pharmacological and gene expression down-regulation interventions were implemented to prevent the production of L-lactate from glycogen-which is exclusively localized in astrocytes-and its release from these cells in the hippocampus during behavioral training (1). Such interventions completely prevented the establishment of LTM and their effect was fully reversed by the intrahippocampal administration of L-lactate during the training session. The fact that glucose at equicaloric concentrations only marginally mimicked the rescuing effect of L-lactate was taken as an unexpected indication that the primary mechanism of action of L-lactate on plasticity mechanisms was independent of its ability to act as an energy substrate. A role of L-lactate in memory processes was also recently shown in other behavioral paradigms (2, 3). We therefore set out to investigate the molecular mechanisms at the basis of the function of L-lactate on neuronal plasticity.Molecular mechanisms underlying both LTM and long-term plasticity include the induction of expression of a group of immediate early genes (IEGs) such as early growth response 1 (Zif268 or Egr1), CCAAT/enhancer binding protein (C/EBP), and proto-oncogene c-Fos (c-Fos) as well as activity-regulated cytoskeletal-associated protein (Arc or Arg3.1) as a direct effector protein at the synapse, which all participate to different physiological processes associated with neuronal p...

show abstract

A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors

Cited by 143 publications

References 41 publications

Contribution of the M1 Transmembrane Helix and Pre-M1 Region to Positive Allosteric Modulation and Gating of N-Methyl-d-Aspartate Receptors

Contribution of the M1 Transmembrane Helix and Pre-M1 Region to Positive Allosteric Modulation and Gating of N-Methyl-d-Aspartate Receptors

Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

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