Inactivation of NMDA Receptors by Direct Interaction of Calmodulin with the NR1 Subunit

  title={Inactivation of NMDA Receptors by Direct Interaction of Calmodulin with the NR1 Subunit},
  author={Michael D. Ehlers and Su Zhang and Jeffrey Bernhardt and Richard L. Huganir},

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Phosphorylation-dependent Regulation ofN-Methyl-d-aspartate Receptors by Calmodulin*
It is found that calmodulin interacts with the COOH terminus of the NR1 subunit and inactivates the channels in a Ca2+-dependent manner, and stimulation of metabotropic glutamate receptor 1α, which potentiates NMDA channels through PKC, decreases the ability of NR1 to bind to cal modulin.
Intracellular domains of NR2 alter calcium-dependent inactivation of N-methyl-D-aspartate receptors.
The molecular basis for NR2-subunit specificity is examined using chimeric and mutated NMDA receptor subunits expressed in HEK293 cells and it is reported that the intracellular loop immediately distal to the pore-forming P-loop M2 (M2-3 loop), as well as a short region in the C terminus, are involved inNR2- subunit specificity.
Direct Effects of Calmodulin on NMDA Receptor Single-Channel Gating in Rat Hippocampal Granule Cells
Calmodulin-dependent inhibition of NMDA receptors will reduce the amplitude and time course of excitatory synaptic currents and thus affect synaptic plasticity and integration of synaptic activity in the CNS.
Competitive binding of α-actinin and calmodulin to the NMDA receptor
The mechanisms by which neurotransmitter receptors are immobilized at postsynaptic sites in neurons are largely unknown. The activity of NMDA (N-methyl-D-aspartate) receptors is mechanosensitive1 and
Mg2+ inhibition of whole-cell NMDA currents in cortical neurons, which express NMDA receptors with NR2A or NR2B NR2 subunits, is very sensitive to ionic conditions and can be explained by a kinetic model which incorporates external permeant ion binding sites within the pore.
Interaction with the NMDA receptor locks CaMKII in an active conformation
It is shown that regulated CaMKII interaction with two sites on the NMDA receptor subunit NR2B provides a mechanism for the glutamate-induced translocation of the kinase to the synapse in hippocampal neurons.
Intracellular Domains of NR 2 Alter Calcium-Dependent Inactivation of N-Methyl-D-aspartate Receptors
The molecular basis for NR2subunit specificity is examined using chimeric and mutated NMDA receptor subunits expressed in HEK293 cells and it is reported that the intracellular loop immediately distal to the pore-forming P-loop M2 (M2–3 loop), as well as a short region in the C terminus, are involved in NR2-sub unit specificity.
Interactions of Calmodulin and α-Actinin with the NR1 Subunit Modulate Ca2+-Dependent Inactivation of NMDA Receptors
It is proposed that inactivation can occur after C0 dissociates from α-actinin by two distinct but converging calcium-dependent processes: competitive displacement ofα-act inin by calmodulin and reduction in the affinity of α-Actinin for C0 after binding of calcium to α- actinin.


Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes
Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% ientical in sequence, and these are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor sub Units.
Changing subunit composition of heteromeric NMDA receptors during development of rat cortex
Direct evidence is presented that NMDA receptors exist in rat neocortex as heteromeric complexes of considerable heterogeneity, some containing both NR2A and NR2B subunits.
Synaptic desensitization of NMDA receptors by calcineurin
Physiological stimulation of NMDA receptors on rat hippocampal neurons resulted in desensitization that was prevented by intracellular 1,2-bis(o-aminophenoxy)ethane-N, N,N,N',N'-tetraacetic acid, adenosine-5'-O-(3-thiotriphosphate) (ATP-gamma-S), or inhibitors of phosphatase 2B (calcineurin).
Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase
In adult neurons, calcineurin, activated by calcium entry through native NMDA channels, shortens the duration of channel openings, which is consistent with the importance of phosphorylation of the NMDA-receptor complex in the short- and long-term control of neuronal excitability.
Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain
Examination of the phosphorylation of the NMDA receptor subunit NMDAR1 (NR1) by protein kinase C (PKC) in cells transiently expressing recombinant NR1 and in primary cultures of cortical neurons provides evidence that the C-terminal domain of the NR1 protein is located intracellularly, suggesting that the proposed transmembrane topology model for glutamate receptors may be incorrect.
Regulated subcellular distribution of the NR1 subunit of the NMDA receptor.
It is demonstrated that amino acid sequences contained within the NR1 molecule serve to localize this receptor subunit to discrete membrane domains in a manner that is regulated by alternative splicing and protein phosphorylation.
NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones
It is directly demonstrated that excitatory amino acids acting at NMDA receptors on spinal cord neurones increase the intracellular Ca2+ activity, measured using the indicator dye arsenazo III, and that this is the result of Ca2- influx through NMDA receptor channels.
Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones
Using voltage-clamp experiments on mouse spinal cord neurones, it is shown that the voltage-sensitivity of NMDA action is greatly reduced on the withdrawal of physiological concentrations (∼1 mM) of Mg2+ from the extracellular fluid, providing further evidence that Mg 2+ blocks inward current flow through ion channels linked to NMDA receptors.
Mammalian ionotropic glutamate receptors
Molecular diversity of the NMDA receptor channel
Findings suggest that the molecular diversity of the ɛ subunit family underlies the functional heterogeneity of the NMDA receptor channel.