Mechanism of NMDA receptor channel block by MK-801 and memantine

Song, Xianqiang; Jensen, Michael Hansen; Jogini, Vishwanath; Stein, Richard A.; Lee, Chia Hsueh; Mchaourab, Hassane S.; Shaw, David E.; Gouaux, Eric

doi:10.1038/s41586-018-0039-9

Cited by 189 publications

(127 citation statements)

References 57 publications

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“…All-atom molecular dynamics (MD) simulations studies have been very successful in describing functional mechanisms of membrane proteins, particularly ion channels [28][29][30][31]. Having an atomic model of claudin pores provides a unique opportunity to test hypotheses about the structural basis of charge-and size-selectivity in claudin pores.…”

Section: Ion Transport Simulationsmentioning

confidence: 99%

Computational Modeling of Claudin Structure and Function

Fuladi

Jannat

Shen

et al. 2020

IJMS

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Tight junctions form a barrier to control passive transport of ions and small molecules across epithelia and endothelia. In addition to forming a barrier, some of claudins control transport properties of tight junctions by forming charge- and size-selective ion channels. It has been suggested claudin monomers can form or incorporate into tight junction strands to form channels. Resolving the crystallographic structure of several claudins in recent years has provided an opportunity to examine structural basis of claudins in tight junctions. Computational and theoretical modeling relying on atomic description of the pore have contributed significantly to our understanding of claudin pores and paracellular transport. In this paper, we review recent computational and mathematical modeling of claudin barrier function. We focus on dynamic modeling of global epithelial barrier function as a function of claudin pores and molecular dynamics studies of claudins leading to a functional model of claudin channels.

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Section: Ion Transport Simulationsmentioning

confidence: 99%

Computational Modeling of Claudin Structure and Function

Fuladi

Jannat

Shen

et al. 2020

IJMS

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“…MK-801 targets the transmembrane domain of the NMDAR and binds at several binding sites of the wellknown psychotomimetic agent phencyclidine [9,10]. This blocks the flow of ions by occluding the permeation pathway and by promoting closure of the ion channel gate [9,11]. Initially, MK-801 was hoped to be harnessed as a potent neuroprotective agent and anti-convulsant [12].…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Dysfunction in Schizophrenia and Aberrant Hippocampal Synaptic Plasticity in Rodent Model Psychosis: a Selective Review

2019

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Schizophrenia is a complex, heterogeneous psychiatric disorder that affects about 1% of the global population. Hippocampal dysfunction has been linked to both cognitive deficits and positive symptoms in schizophrenia. Here, we briefly review current findings on disrupted hippocampal processing from a clinical perspective before concentrating on preclinical studies of aberrant hippocampal synaptic plasticity using the N-methyl-D-aspartate receptor hypofunction model of psychosis and related findings from genetic models. Taken together, the results put the case for maladaptive hippocampal synaptic plasticity and its extrinsic connections as mechanistic underpinnings of cognitive impairments in schizophrenia.

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“…The experimental data suggest voltage‐dependent binding of pentamidine and diminazene in the pore of NMDA receptors but with different mechanisms. To rationalize these results in structural terms, we docked pentamidine and diminazene in the recently published (Song et al, ) closed‐state structure (pdb code 5un1) that was obtained in the complex with MK‐801. A total of 10,000 random orientations of the drugs molecules in the channel cavity were generated and optimized in short MCM trajectories (20 steps) to eliminate sterical clashes.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of NMDA receptor inhibition by diarylamidine compounds

Dron

Zhigulin

Barygin

2019

Eur J of Neuroscience

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Pentamidine, diminazene and 4′,6‐diamidino‐2‐phenylindole (DAPI) are antiprotozoal diarylamidine compounds. In the present work, we have studied their action on native N‐methyl‐D‐aspartate (NMDA) receptors in rat hippocampal pyramidal neurons. All three compounds inhibited NMDA receptors at −80 mV holding voltage with IC50 of 0.41 ± 0.08, 13 ± 3 and 3.1 ± 0.6 μM, respectively. The inhibition by pentamidine was strongly voltage‐dependent, while that of DAPI was practically voltage‐independent. Inhibition by diminazene had both voltage‐dependent and voltage‐independent components. Diminazene and DAPI demonstrated tail currents and overshoots suggesting “foot‐in‐the‐door” mechanism of action. In contrast, pentamidine was partially trapped in the closed NMDA receptor channels. Such difference in the mechanism of action can be explained by the difference in the 3D structure of compounds. In the pentamidine molecule, two benzamidine groups are connected with a flexible linker, which allows the molecule to fold up and fit in the cavity of a closed NMDA receptor channel. Diminazene and DAPI, in contrast, have an extended form and could not be trapped.

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Mechanism of NMDA receptor channel block by MK-801 and memantine

Cited by 189 publications

References 57 publications

Computational Modeling of Claudin Structure and Function

Computational Modeling of Claudin Structure and Function

Hippocampal Dysfunction in Schizophrenia and Aberrant Hippocampal Synaptic Plasticity in Rodent Model Psychosis: a Selective Review

Mechanisms of NMDA receptor inhibition by diarylamidine compounds

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