Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors

Regan, Michael C.; Zhu, Zongjian; Yuan, Hongjie; Myers, Scott J.; S., Menaldino, Dave; Tahirovic, Yesim A.; Liotta, Dennis; Traynelis, Stephen F.; Furukawa, Hiro

doi:10.1038/s41467-019-08291-1

Cited by 35 publications

(30 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, this mechanism of inhibition is well supported by published crystal structures of seven different ligands from the 93-series (PDB 6E7R-6E7X) showing all π/π-interactions with GluN2B F176 with distances between ligand and phenyl ring less than 5.0 Å 36 .…”

Section: Discussionsupporting

confidence: 65%

A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors

et al. 2019

View full text Add to dashboard Cite

N-methyl-D-aspartate receptors (NMDARs), especially GluN2B-containing NMDARs, are associated with neurodegenerative diseases like Parkinson, Alzheimer and Huntington based on their high Ca2+ conductivity. Overactivation leads to high intracellular Ca2+ concentrations and cell death rendering GluN2B-selective inhibitors as promising drug candidates. Ifenprodil represents the first highly potent prototypical, subtype-selective inhibitor of GluN2B-containing NMDARs. However, activity of ifenprodil on serotonergic, adrenergic and sigma receptors limits its therapeutic use. Structural reorganization of the ifenprodil scaffold to obtain 3-benzazepines retained inhibitory GluN2B activity but decreased the affinity at the mentioned non-NMDARs. While scaffold optimization improves the selectivity, the molecular inhibitory mechanism of these compounds is still not known. Here, we show a common inhibitory mechanism of ifenprodil and the related 3-benzazepines by mutational modifications of the receptor binding site, chemical modifications of the 3-benzazepine scaffold and subsequent in silico simulation of the inhibitory mechanism.

show abstract

Section: Discussionsupporting

confidence: 65%

A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors

et al. 2019

View full text Add to dashboard Cite

show abstract

“…2019; Regan et al . 2019). The relative positioning of these two bilobed domains within the complex varies across the receptor family, which drives unique structural features of subfamilies as well as unique functional attributes.…”

Section: Introductionmentioning

confidence: 99%

Hodgkin–Huxley–Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif

Perszyk

Myers

Yuan

et al. 2020

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Glutamate receptors are essential ligand-gated ion channels in the central nervous system that mediate excitatory synaptic transmission in response to the release of glutamate from presynaptic terminals. The structural and biophysical basis underlying the function of these receptors has been studied for decades by a wide range of approaches. However recent structural, pharmacological and genetic studies have provided new insight into the regions of this protein that are critical determinants of receptor function. Lack of variation in specific areas of the protein amino acid sequences in the human population has defined three regions in each receptor subunit that are under selective pressure, which has focused research efforts and driven new hypotheses. In addition, these three closely positioned elements reside near a cavity that is shown by multiple studies to be a likely site of action for allosteric modulators, one of which is currently in use as an FDA-approved anticonvulsant. These structural elements are capable of controlling gating of the pore, and appear to permit some modulators bound within the cavity to also alter permeation properties. This creates a new precedent whereby features of the channel pore can be modulated by exogenous drugs that bind outside the pore. The convergence of structural, genetic, biophysical and pharmacological approaches is a powerful means to gain insight into the complex biological processes defined by neurotransmitter receptor function.

show abstract

“…Scanned images were imported into NimbleScan software (version 2.5) for grid alignment and expression data analysis. Expression data were normalized through quantile normalization and the Robust Multichip Average (Regan et al, 2019 ) algorithm in the NimbleScan software. All gene-level files were imported into Agilent GeneSpring GX software (version 11.5.1, USA) for further analysis.…”

Section: Methodsmentioning

confidence: 99%

COX5A Plays a Vital Role in Memory Impairment Associated With Brain Aging via the BDNF/ERK1/2 Signaling Pathway

Xiyang

Liu

Wang

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

Cytochrome c oxidase subunit Va (COX5A) is involved in maintaining normal mitochondrial function. However, little is known on the role of COX5A in the development and progress of Alzheimer's disease (Martinez-Losa et al., 2018). In this study, we established and characterized the genomic profiles of genes expressed in the hippocampus of Senescence-Accelerated Mouse-prone 8 (SAMP8) mice, and revealed differential expression of COX5A among 12-month-aged SAMP8 mice and 2-month-aged SAMP8 mice. Newly established transgenic mice with systemic COX5A overexpression (51% increase) resulted in the improvement of spatial recognition memory and hippocampal synaptic plasticity, recovery of hippocampal CA1 dendrites, and activation of the BDNF/ERK1/2 signaling pathway in vivo. Moreover, mice with both COX5A overexpression and BDNF knockdown showed a poor recovery in spatial recognition memory as well as a decrease in spine density and branching of dendrites in CA1, when compared to mice that only overexpressed COX5A. In vitro studies supported that COX5A affected neuronal growth via BDNF. In summary, this study was the first to show that COX5A in the hippocampus plays a vital role in aging-related cognitive deterioration via BDNF/ERK1/2 regulation, and suggested that COX5A may be a potential target for anti-senescence drugs.

show abstract

Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors

Cited by 35 publications

References 38 publications

A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors

A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors

Hodgkin–Huxley–Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif

COX5A Plays a Vital Role in Memory Impairment Associated With Brain Aging via the BDNF/ERK1/2 Signaling Pathway

Contact Info

Product

Resources

About