THE STRUCTURAL SPECIFICITY OF THE HIGH AFFINITY UPTAKE OF <scp>l</scp>‐GLUTAMATE AND <scp>l</scp>‐ASPARTATE BY RAT BRAIN SLICES

Balcar, Vladimír J.; Johnston, Graham A.R.

doi:10.1111/j.1471-4159.1972.tb01325.x

Cited by 678 publications

(285 citation statements)

References 37 publications

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“…We show, as previously demonstrated by other investigators (12)(13)(14)(15)(16), that L-aspartate and L-glutamate depolarize the horizontal cells and thus mimic the photoreceptor transmitter. Though the amino acids produce this effect only at millimolar concentrations, the response to L-glutamate can be potentiated approximately 15-fold by exposure to D-aspartate, a substance that has been shown to produce a competitive inhibition of L-glutamate uptake (17). Because D-aspartate also appears to augment the light responses of horizontal cells, our results are consistent with the possibility that L-glutamate is a synaptic transmitter in goldfish cones.…”

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confidence: 79%

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D-aspartate potentiates the effects of L-glutamate on horizontal cells in goldfish retina.

Ishida

Fain

1981

Proc. Natl. Acad. Sci. U.S.A.

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The amino acids L-glutamate and L-aspartate depolarize HI horizontal cells in the perfused goldfish retina but only at millimolar concentrations. The effects of L-glutamate (but not of L-aspartate) are potentiated approximately 15-fold by exposure to D-aspartate. D-Aspartate blocks acidic amino acid uptake in goldfish retina, so that the potentiation ofL-glutamate may be produced by an increase in its effective concentration at the horizontal cell membrane. Because D-aspartate also augments the light responses of horizontal cells, our results are consistent with the possibility that L-glutamate is a neurotransmitter of cone photoreceptors in goldfish.Since the demonstration of the effects of amino acids on motoneurons nearly 20 years ago (1, 2), much attention has been given to the possibility that L-glutamate, L-aspartate, and other structurally similar acidic amino acids may function as synaptic transmitters in the vertebrate central nervous system. Exogenously applied L-glutamate has been shown to produce a depolarization or increase in spike firing in neurons from a variety of structures, including the cortex, hippocampus, cochlear nucleus, and thalamus (3). A Ca2+-dependent release of L-glutamate or L-aspartate has been demonstrated in several preparations, and there is evidence for a Na+-dependent, highaffinity uptake system for acidic amino acids in glia and some neurons (3)(4)(5).In spite of these findings, there is still considerable uncertainty whether L-glutamate or L-aspartate actually functions as a synaptic transmitter in vertebrates. Part of the reason for this is that these substances produce effects only at rather high concentrations and are usually nonspecific (6). Neurons depolarized by L-glutamate or by L-aspartate are usually also affected (and at similar concentrations) by D isomers of amino acids and by a large number of structurally similar analogues (2, 7). It seems possible that these compounds are not all reacting with the same membrane receptor (7,8) The retina offers several advantages for the study of synaptic transmitter mechanisms. Because it is possible in certain poikilotherms to remove the retina from its surrounding tissue and to maintain it in artificial media, it is possible to add amino acids and other drugs directly to the Ringer's solution. This reduces the uncertainty in estimates of drug concentration at the postsynaptic membrane. Furthermore, the retina is considerably simpler in structure than most of the rest of the central nervous system and has been extensively studied, both anatomically and physiologically (9). This is especially true for the outer plexiform layer, where photoreceptors synapse onto two kinds of secondorder cells, the horizontal cell and the bipolar cell (10).In this study we describe the effects of amino acids on one of the types of horizontal cells in the goldfish retina. This cell, called the H1 (or luminosity-type) cell, receives most of its synaptic input from the cone photoreceptors, predominantly those containing the red-sensitive p...

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confidence: 79%

“…1 did not reflect the actual concentrations at the postsynaptic membrane. To test this notion, we attempted to block uptake by exposing the retina to D-aspartate, which has been shown to be an inhibitor of acidic amino acid uptake in retina (27) and cerebral cortex (17).…”

Section: Effects Of L"mentioning

confidence: 99%

D-aspartate potentiates the effects of L-glutamate on horizontal cells in goldfish retina.

Ishida

Fain

1981

Proc. Natl. Acad. Sci. U.S.A.

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“…It should be noted that the chloride-and calcium-sensitive Glu transport system is pharmacologically distinct from the classical Na + -and D-aspartate-sensitive Glu uptake site. There is currently no data on the action of L-PSer on this Glu uptake system but L-AP4 does not block Na ' -dependent Glu uptake (Balcar and Johnston, 1972;Vincent and McGeer, 1980;Monaghan et al, 1983). Data on the action of L-PSer at the Nat-dependent Glu uptake site would be helpful in gaining a better understanding of the pharmacology and physiology of this metabolite.…”

Section: Discussionmentioning

confidence: 99%

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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“…In addition, extirpation of the entire hippocampus, destruction of the hippocampal pyramids with kainic acid, or transection of the fi-fx pathway markedly reduced the amount of endogenous glutamate (GLU) and the high-affinity uptake of this amino acid in the dorsolateral septum (13,25,30,32,34). In that experimental design, however, the uptake mechanism of GLU does not distinguish between GLU-and aspartate (ASP)-using fibers (2).…”

Section: Electrophysiologicalmentioning

confidence: 95%

Amino acid neurotransmission between fimbria-fornix fibers and neurons in the lateral septum of the rat: A microiontophoretic study

Joëls¹,

Urban²

1984

Experimental Neurology

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We investigated the nature of the excitatory amino acid and the type of amino acid receptor involved in the projection of fimbria-fomix (fi-fx) fibers on neurons in the lateral septal complex (LSC) of the rat. It appeared that neurons which were strongly orthodromically activated (SOA) by stimulation of fi-fx fibers were excited by glutamate (GLU) and aspartate (ASP) at much lower ejecting currents than neurons which were only weakly orthodromically excited. In addition, GLU was a stronger agent than ASP, particularly in SOA septal cells. Two amino acid antagonists tested, glutamic acid diethylester (GDEE) and 2-amino-S-phosphonovaleric acid (2-APV), selectively antagonized responses to the amino acid agonists quisqualate (QUIS) and N-methyl-D-aspartate (NMDA), respectively. They also depressed GLU-and ASP-induced responses, although in that case the antagonists frequently had to be expelled with currents higher than those needed to block QUIS-and NMDA-evoked excitations. Furthermore, GDEE frequently antagonized GLU-induced responses better than ASPevoked excitations, whereas 2-APV often blocked responses to ASP more effectively than those to GLU. It was observed that GDEE, ejected with currents that blocked responses to QUIS reversibly, decreased the number of synaptic responses induced in SOA cells by fi-fx stimuli. Synaptically induced excitation in these neurons was consistently una&cted by 2-APV, even when the antagonist was expelled with high currents. According to these results, LSC neurons, in particular the SOA neurons, are more Abbreviations: li-fx-fimbria-fomix; LSC-lateral septal complex; SOA, WOA-strongly, weakly orthodromically activated; GLU-glutamate; ASP-aspartate; GDEE-glutamic acid diethylester, 2-APV-2-amino%phosphonovaleric acid; QUIS-quisqualate; NMDA-N-methylDaspartate; KA-kainic acid.

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THE STRUCTURAL SPECIFICITY OF THE HIGH AFFINITY UPTAKE OF l‐GLUTAMATE AND l‐ASPARTATE BY RAT BRAIN SLICES

Cited by 678 publications

References 37 publications

D-aspartate potentiates the effects of L-glutamate on horizontal cells in goldfish retina.

D-aspartate potentiates the effects of L-glutamate on horizontal cells in goldfish retina.

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

Amino acid neurotransmission between fimbria-fornix fibers and neurons in the lateral septum of the rat: A microiontophoretic study

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