L-Glutamate has higher affinity than other amino acids for [3H]-D-AP5 binding sites in rat brain membranes

Olverman, Henry J.; Jones, Arwel W.; Watkins, Johnathan

doi:10.1038/307460a0

Cited by 291 publications

(121 citation statements)

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“…Although the binding data of Olverman et al (1984) suggest that the affinity of glutamate for D-APV binding sites approaches that of D-APV itself, we think it likely that these high concentrations of APV or D-APV effectively blocked 500 PM glutamate from activating most of the physiologically relevant NMDA receptors. O'Brien and Fischbath (1986) found 1 mM APV to be sufficient to eliminate the voltage-dependent component of the response to 1 mM glutamate on chick spinal motoneurons.…”

Section: Discussionmentioning

confidence: 99%

“…NMDA-activated membrane channels are thought to exhibit a number of special properties, including susceptibility to blockade by magnesium at hyperpolarized membrane potentials Nowak et al, 1984), rapid desensitization (Zorumski and Fischbach, 1985), and high calcium permeability Mayer et al, 1986). Although glutamate has a high affinity for the NMDA receptor (Olverman et al, 1984) magnesium blockade (at least near resting membrane potentials) and desensitization probably act to limit the contribution of NMDA channels, relative to that of QUIS and RAIN channels, to glutamate neuroexcitation. Glutamate neuroexcitation is thus completely blocked by high concentrations of broad spectrum antagonists such as kynurenate (Ganong et al, 1983;Jahr and Jessel, 1985;Huettner and Baughman, 1986) but is only partially attenuated by selective NMDA antagonists (Watkins and Evans, 1981;O'Brien and Fischbach, 1986).…”

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confidence: 99%

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Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

1988

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The antagonist pharmacology of glutamate neurotoxicity was quantitatively examined in murine cortical cell cultures. Addition of 1- 3 mM DL-2-amino-5-phosphonovalerate (APV), or its active isomer D-APV, acutely to the exposure solution selectively blocked the neuroexcitation and neuronal cell selectively blocked the neuroexcitation and neuronal cell loss produced by N-methyl-D-aspartate (NMDA), with relatively little effect on that produced by either kainate or quisqualate. As expected, this selective NMDA receptor blockade only partially reduced the neuroexcitation or acute neuronal swelling produced by the broad-spectrum agonist glutamate; surprisingly, however, this blockade was sufficient to reduce glutamate- induced neuronal cell loss markedly. Lower concentrations of APV or D- APV had much less protective effect, suggesting that the blockade of a large number of NMDA receptors was required to acutely antagonize glutamate neurotoxicity. This requirement may be caused by the amplification of small amounts of acute glutamate-induced injury by subsequent release of endogenous NMDA agonists from injured neurons, as the “late” addition of 10–1000 microM APV or D-APV (after termination of glutamate exposure) also reduced resultant neuronal damage. If APV or D-APV were present both during and after glutamate exposure, a summation dose-protection relationship was obtained, showing substantial protective efficacy at low micromolar antagonist concentrations. Screening of several other excitatory amino acid antagonists confirmed that the ability to antagonize glutamate neurotoxicity might correlate with ability to block NMDA-induced neuroexcitation: The reported NMDA antagonists ketamine and DL-2-amino- 7-phosphono-heptanoate, as well as the broad-spectrum antagonist kynurenate, were all found to attenuate glutamate neurotoxicity substantially; whereas gamma-D-glutamylaminomethyl sulfonate and L- glutamate diethyl ester, compounds reported to block predominantly quisqualate or kainate receptors, did not affect glutamate neurotoxicity. The present study suggests that glutamate neurotoxicity may be predominantly mediated by the activation of the NMDA subclass of glutamate receptors--occurring both directly, during exposure to exogenous compound, and indirectly, due to the subsequent release of endogenous NMDA agonists. Given other studies linking NMDA receptors to channels with unusually high calcium permeability, this suggestion is consistent with previous data showing that glutamate neurotoxicity depends heavily on extracellular calcium.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

1988

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“…If G1 receptors have a relatively high affinity for glutamate (19), a response that slowly rises and decays implies that there might be a 'significant population of extrasynaptic receptors.…”

Section: Methodsmentioning

confidence: 99%

Rapid desensitization of glutamate receptors in vertebrate central neurons.

Trussell¹,

Thio²,

Zorumski³

et al. 1988

Proceedings of the National Academy of Sciences

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We have examined glutamate receptor desensitization in voltage-clamped embryonic chicken spinal cord neurons and postnatal rat hippocampal neurons maintained in culture. Rapid currents that rose in 0.8-3.6 msec were evoked when glutamate was ionophoresed with 0.5-to 1.0-msec pulses. With prolonged pulses or brief, repetitive pulses, glutamate-evoked currents decayed rapidly in a manner that was independent of holding potential. A similar desensitization occurred following close-range pressure ejection of glutamate. The rapid, desensitizing glutamate current exhibited a linear current-voltage relation and it was not blocked by 2-amino-5-phosphonovalerate, suggesting that it was mediated by N-methyl-D-aspartate-insensitive (G2) receptors. Desensitization of G2 receptors may be agonist-dependent: currents evoked by kainate, a selective G2 agonist, did not decay, whereas prior application of glutamate did reduce the size of kainate responses. The appearance of the rapid current depended critically on the position of the ionophoretic pipette. Such glutamate-receptor "hot spots" often corresponded to points of contact with neighboring neurites, which raises the possibility that they are located at synapses.Glutamate is considered to be a "mixed agonist" in that it activates more than one type of receptor. The most common classification of glutamate receptors is based on the relative efficacy of three agonists: N-methyl-D-aspartate (N-Me-DAsp), kainate, and quisqualate (1-4). In chicken spinal cord neurons, kainate and quisqualate appear to compete for the same site, so we refer to only two' broad categories (2): G1 receptors are activated by N-Me-D-Asp and blocked by 2-amino-5-phosphonovalerate (APV) and Mg2 + (the latter in a voltage-dependent manner); G2 receptors are activated by kainate and quisqualate. In addition, G1, but not G2, currents are desensitized following prolonged or repeated application of glutamate (or more selective agonists) over a period of several seconds (5).It is important to determine whether receptor desensitization occurs on the time scale of synaptic transmission. Our previous studies did not address this issue because the agonists were applied by pressure ejection from pipettes located 25-50 ,um away from the target neuron (2,5,6). In this situation, the buildup of agonist concentration at the receptor sites is slow compared to the time course of synaptically released transmitter. In addition, such a diffuse application must activate extrasynaptic as well as synaptic receptors.In this study, we examined rapid desensitization following focal ionophoresis or close-range pressure ejection of glutamate and other agonists. Responses evoked at extremely sensitive sites (hot spots) on the neuronal surface were desensitized rapidly. The desensitizing currents were not blocked by APV. These data suggest that G2 receptors are, in fact, desensitized but with a time course that is >2 orders of magnitude faster than G1 receptor desensitization. Some of these results have been presented in abst...

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“…D-PSer had a K1 of 303 pM in the same assay. Olverman et al (1984Olverman et al ( , 1988 showed L-PSer to be a weak inhibiter of D- [3H]2-amino-5-phosphonopentanoiC acid (AP5) with an Ki of approx 1 mM. Likewise, Murphy et -al.…”

Section: Binding Studiesmentioning

confidence: 96%

Possible roles ofl-phosphoserine in the pathogenesis of Alzheimer’s disease

Klunk

McClure

Pettegrew

1991

Molecular and Chemical Neuropathology

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L-PhOSphoseflne is a membrane metabolite that is elevated in Alzheimer's disease brain. This compound has close structural similarity to L-glutamate. Electrophysiological studies indicate that L-phosphoserme has an acute inhibitory effect, but a delayed excitatory action. A hypothesis is developed based on pharmacological and electrophysiological studies that suggest that the inhibition may be mediated through presyrtaptic inhibition of L-glutamate release or perhaps antagonism of postsynaptic kainic acid receptors. The mechanism of the delayed excitation may lie in the tendency of L-phosphoserine to mimic the action of L-2-amino-4-phosphOnobutyric acid, a blocker of chloride-and calcium-sensitive L-glutamate transport. L-PhosphOserine has also been found to be a competitive antagonist at the N-methyl-o-aspartate recognition site and an antagonist of metabotropic receptor-mediated hydrolysis of inositol phospholipids. Because of these actions, there are several potentially important implications for the elevation of L-phosphoserme in Alzheimer's disease, including production memory impairment through presyn-

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L-Glutamate has higher affinity than other amino acids for [3H]-D-AP5 binding sites in rat brain membranes

Cited by 291 publications

References 16 publications

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

Rapid desensitization of glutamate receptors in vertebrate central neurons.

Possible roles ofl-phosphoserine in the pathogenesis of Alzheimer’s disease

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