Calmodulin Mediates Calcium-Dependent Inactivation of N-Methyl-D-Aspartate Receptors

Zhang, Su; Ehlers, Michael; Bernhardt, Jeffery P.; Su, Ching Tien; Huganir, Richard L.

doi:10.1016/s0896-6273(00)80553-x

Cited by 258 publications

(258 citation statements)

References 47 publications

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“…This effect would be predicted to reduce the number of NMDA receptors in the activated state (Yu and Salter 1998). Alternatively, perhaps by attenuating intracellular calcium levels, nimodipine may have influenced the phosphorylation state of NMDA receptor subunits and reduced the ketamine sensitivity of these receptors (Zhang et al 1998). A third possibility is that nimodipine and ketamine interacted through opposing modulation of the function of intracellular phosphoproteins, such as calmodulin or cAMP response element-binding protein, whose function might be directly or indireclty sensitive to calcium (CREB) (Deisseroth et al 1998;Ghosh et al 1994;Mermelstein et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Krupitsky

2001

Neuropsychopharmacology

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Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/ kg/hr) (Krystal et al. 1999c). In addition, these drugs produce effects in healthy human subjects that resemble aspects of the signs and symptoms of schizophrenia or dissociative disorders (Krystal et al. 25 , NO . 6 Nimodipine-Ketamine Interactions 937 1999a). As a result, ketamine administration may provide a laboratory-based approach that may contribute to the characterization of NMDA receptor contributions to cognitive function and the development of novel pharmacotherapeutic approaches that might ameliorate the consequences of NMDA receptor dysfunction. NMDA receptor antagonists also have ethanol-like behavioral effects in animals and humans (Grant and Colombo 1993;Krystal et al. 1998b;Petrakis et al. 2001). In ethanol dependent patients, ketamine effects were deemed more similar to ethanol effects than they were to the effects of marijuana or cocaine (Krystal et al. 1998b). This observation is consistent with studies indicating that NMDA receptors are among the highest affinity targets of ethanol in the brain, where it produces dose-related uncompetitive antagonism of receptor function (Grant and Lovinger 1995;Lovinger 1997). In animals, the behavioral effects of ethanol have a complex neurobiology, reflecting the interaction of the many component dose-related actions of ethanol in the brain (Green and Grant 1998).Ethanol, relative to the uncompetitive NMDA receptor antagonists phencyclidine and ketamine, has less propensity to produce psychotic symptoms in healthy humans or recovering ethanol-dependent patients (Krystal et al. 1994a;Krystal et al. 1998b;Luby et al. 1959). The limited psychotogenic propensity of ethanol at doses typically associated with human intoxication may reflect the capacity of ethanol facilitation of GABA A receptor function to moderate its NMDA antagonist effects (Grant and Lovinger 1995). Consistent with this hypothesis, some reduction in the perceptual effects of ketamine in healthy human subjects was produced by lorazepam pretreatment (Krystal et al. 1998a). However, preclinical data suggest that the capacity of ethanol to block L-type VSCCs (Crews et al. 1996) may also protect against its psychotogenic potential. In animals, components of the behavioral and discriminative stimulus effects of NMDA antagonists are attenuated by pretreatment with L-type VSCC antagonists (Green and Grant 1999;Green-Jordan and Grant 2000;Popoli et al. 1992;Sukhotina et al. 1999).The current ...

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Section: Discussionmentioning

confidence: 99%

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Krupitsky

2001

Neuropsychopharmacology

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“…An alternative explanation is that the C-terminal domain has different configurations, which depend on its dynamic interactions with the cytoskeleton. In support of this intriguing possibility, it has been shown that the binding of NR1 to ␣-actinin is displaced by calmodulin (Wyszynski et al, 1997), a process that might explain the calcium-dependent inactivation of NMDA receptors (Ehlers et al, 1996;Zhang et al, 1998;Krupp et al, 1999).…”

Section: Subsynaptic Organization Of Glutamate Receptorsmentioning

confidence: 95%

Organization of Ionotropic Glutamate Receptors at Dendrodendritic Synapses in the Rat Olfactory Bulb

Sassoè‐Pognetto

Ottersen

2000

J. Neurosci.

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Dendrodendritic synapses between mitral (or tufted) and granule cells of the olfactory bulb play a major role in the processes of odor discrimination and olfactory learning. Release of glutamate at these synapses activates postsynaptic receptors on the dendritic spines of granule cells, as well as presynaptic NMDA receptors in the mitral cell membrane. However, immunocytochemical studies have failed to demonstrate the presence of ionotropic glutamate receptors in granule cell dendrites. By using a postembedding immunogold procedure, we describe here the precise organization of neurotransmitter receptors at dendrodendritic synapses. We show that there is a selective localization of glutamate and GABA receptors at asymmetric and symmetric synaptic junctions, respectively. In addition, we demonstrate that NMDA and AMPA receptors are clustered at postsynaptic specializations on granule cell spines and that they are extensively colocalized. Conversely, glutamate receptors do not appear to be concentrated in clusters on mitral cell dendrites, suggesting that the presynaptic effects of glutamate are mediated by a small complement of extrasynaptic receptors. By analyzing the subsynaptic distribution of the NR1 and GluR2/3 subunits, we show that they are distributed along the entire extent of the postsynaptic specialization, indicating that both NMDA and AMPA receptors are available for dendrodendritic signaling between mitral and granule cells. These results indicate that the principles recently found to underlie the organization of glutamate receptors at axospinous synapses also apply to dendrodendritic synapses.

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“…This suggests that an allosteric rather than a channelblocking (Zhang et al, 1998) mechanism is involved in inhibition of single NMDA channel activity by calmodulin. For example, characteristic NMDA channel block, such as that observed with magnesium, is recognized by a distinct fingerprint alteration of the single-channel shut-time distribution (Ascher and Nowak, 1988;Antonov and Johnson, 1999).…”

Section: Inhibition Of Nmda Receptor Single-channel Activity By Calmomentioning

confidence: 99%

“…Several calcium-dependent proteins associated with the postsynaptic density alter NMDA receptor activity, including calmodulin (CaM) (Ehlers et al, 1996;Hisatsune et al, 1997, Rafiki et al, 1997Zhang et al, 1998;Krupp et al, 1999), calcineurin (Lieberman and Mody, 1994;Tong and Jahr, 1994;Tong et al, 1995), protein kinase C (PKC) (Chen and Huang, 1992;Wagner and Leonard, 1996;Xiong et al, 1998;Lu et al, 2000;Lan et al, 2001), and ␣-actinin-2 (Wyszynski et al, 1997;Zhang et al, 1998;Krupp et al, 1999). Therefore, it is generally acknowledged that calcium influx, in part through the NMDA channel, can regulate NMDA receptor activity via various pathways.…”

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confidence: 99%

Direct Effects of Calmodulin on NMDA Receptor Single-Channel Gating in Rat Hippocampal Granule Cells

Rycroft

Gibb

2002

J. Neurosci.

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NMDA receptors are glutamate-sensitive ion channel receptors that mediate excitatory synaptic transmission and are widely implicated in synaptic plasticity and integration of synaptic activity in the CNS. This is in part attributable to the high calcium permeability of the ion channel, which allows receptor activation to influence the intracellular calcium concentration and also the slow time course of NMDA receptor-mediated synaptic currents. NMDA receptor activity is also regulated by the intracellular calcium concentration through activation of various calcium-dependent proteins, including calmodulin, calcineurin, protein kinase C, and ␣-actinin-2. Here, we have shown that calmodulin reduces the duration of native NMDA receptor single-channel openings from 3.5 Ϯ 0.6 msec to 1.71 Ϯ 0.2 msec in agreement with previous studies on recombinant NMDA receptors (Ehlers et al., 1996). NMDA receptor single-channel amplitudes and shut times were not affected.However, calmodulin reduced the duration of groups of channel openings called superclusters, which determine the slow time course of synaptic currents, from 121 Ϯ 25.4 msec to 60.4 Ϯ 11.6 msec. In addition, total open time, number of channel openings, and charge transfer per supercluster were all reduced by calmodulin. A 68% decrease in charge transfer per supercluster suggests that calmodulin activation will significantly reduce calcium influx during synaptic transmission. These results suggest that 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.

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Calmodulin Mediates Calcium-Dependent Inactivation of N-Methyl-D-Aspartate Receptors

Cited by 258 publications

References 47 publications

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Organization of Ionotropic Glutamate Receptors at Dendrodendritic Synapses in the Rat Olfactory Bulb

Direct Effects of Calmodulin on NMDA Receptor Single-Channel Gating in Rat Hippocampal Granule Cells

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