Kinetic models for activation and modulation of NMDA receptor subtypes

Iacobucci, Gary J.; Popescu, Gabriela

doi:10.1016/j.cophys.2018.02.002

Cited by 19 publications

(21 citation statements)

References 58 publications

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“…Single channel analysis and kinetic modelling indicate that following binding of the agonists, the receptors clearly undergo at least two additional rate‐limiting conformational changes that precede explosive opening of the pore (Fig. 2 C ), which yields step changes in current as the channel opens and closes (Iacobucci & Popescu, 2018). This is supported by structural data for AMPA receptors, one of such intermediate conformations is likely represented by the structures with partially closed agonist‐bound ABDs and non‐conducting closed channel pore (Durr et al .…”

Section: Recent Structural Data Illuminate Key Features In Channel Gamentioning

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

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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.

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Section: Recent Structural Data Illuminate Key Features In Channel Gamentioning

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

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“…The NMDA-Rs consist of several subunits forming heterotetrameric complexes (Feng et al, 2004;Tarnok et al, 2008), and contain a channel largely permeable to Ca 2+ (Paoletti et al, 2013). Functional NMDA-Rs are formed by the combination of GluN1 and at least one GluN2 subunit, or GluN1 in combination with GluN2 and GluN3 subunits (Iacobucci and Popescu, 2018;Kew and Kemp, 2005). Similar to the cerebellum in vivo, the expression of subunits in cultures of cerebellar granule neurons (CGNs) in vitro changes with time, and maturation of the neuronal cultures (Cebers et al, 2001;Vallano et al, 1996).…”

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confidence: 99%

PFOS-induced excitotoxicity is dependent on Ca2+ influx via NMDA receptors in rat cerebellar granule neurons

Berntsen

Bjørklund

Strandabø

et al. 2018

Toxicology and Applied Pharmacology

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Perfluoroalkyl acids (PFAAs) are persistent compounds used in many industrial as well as consumer products. Despite restrictions, these compounds are found at measurable concentrations in samples of human and animal origin. In the present study we examined whether the effects on cell viability of two sulfonated and four carboxylated PFAAs in cultures of cerebellar granule neurons (CGNs), could be associated with deleterious activation of the N-methyl-d-aspartate receptor (NMDA-R). PFAA-induced effects on viability in rat CGNs and unstimulated PC12 cells were examined using the MTT assay. Cells from the PC12 rat pheochromocytoma cell line lack the expression of functional NMDA-Rs and were used to verify lower toxicity of perfluorooctanesulfonic acid (PFOS) in cells not expressing NMDA-Rs. Protective effects of NMDA-R antagonists, and extracellular as well as intracellular Ca chelators were investigated. Cytosolic Ca ([Ca]) was measured using Fura-2. In rat CGNs the effects of the NMDA-R antagonists MK-801, memantine and CPP indicated involvement of the NMDA-R in the decreased viability induced by PFOS and perfluorohexanesulfonic acid (PFHxS). No effects were associated with the four carboxylated PFAAs studied. Further, EGTA and CPP protected against PFOS-induced decreases in cell viability, whereas no protection was afforded by BAPTA-AM. [Ca] significantly increased after exposure to PFOS, and this increase was completely blocked by MK-801. In PC12 cells a higher concentration of PFOS was required to induce equivalent levels of toxicity as compared to in rat CGNs. PFOS-induced toxicity in PC12 cells was not affected by CPP. In conclusion, PFOS at the tested concentrations induces excitotoxicity in rat CGNs, which likely involves influx of extracellular Ca via the NMDA-R. This effect can be blocked by specific NMDA-R antagonists.

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“…Simulations -Macroscopic traces were simulated in QuB or MATLAB software, in response to square jumps into 1 mM glutamate, as the sum of time-dependent open state occupancies, using the experimentally determined microscopic rate constants for the best fitting models. Previously reported microscopic rates for glutamate binding and dissociation rate constants of wild-type receptors were used: 2 x 10 7 M -1 s -1 and 60 s -1 , for N1/N2A (68) and 6 x 10 6 M -1 s -1 and 15 s -1 , for N1/N2B (1,46,50). Simulated traces were analyzed in a manner similar to experimental macroscopic traces.…”

Section: Methodsmentioning

confidence: 99%

Contributions by N-terminal Domains to NMDA Receptor Currents

Amico-Ruvio

Paganelli

Abbott

et al. 2020

Preprint

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To investigate the role of the N-terminal do-mains (NTDs) in NMDA receptor signaling we used kinetic analyses of one-channel currents and compared the reaction mechanism of re-combinant wild-type GluN1/GluN2A and GluN1/GluN2B receptors with those observed for NDT-lacking receptors. We found that trun-cated receptors maintained the fundamental gat-ing mechanism characteristic of NMDA recep-tors, which includes a multi-state activation se-quence, desensitization steps, and mode transi-tions. This result establishes that none of the functionally-defined NMDA receptor activation events require the NTD. Notably, receptors that lacked the entire NTD layer retained isoform-specific kinetics. Together with previous reports, these results demonstrate that the entire gating machinery of NMDA receptors resides within a core domain that contains the ligand-binding and the channel-forming transmembrane domains, whereas the NTD and C-terminal layers serve modulatory functions, exclusively

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Kinetic models for activation and modulation of NMDA receptor subtypes

Cited by 19 publications

References 58 publications

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

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

PFOS-induced excitotoxicity is dependent on Ca2+ influx via NMDA receptors in rat cerebellar granule neurons

Contributions by N-terminal Domains to NMDA Receptor Currents

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