Stereospecific synthesis of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, a selective agonist of metabotropic glutamate receptors

Molitor, Scott C. and Paul B. Manis. Evidence for functional metabotropic glutamate receptors in the dorsal cochlear nucleus. J. Neurophysiol. 77: 1889–1905, 1997. The parallel fibers (PFs) of the dorsal cochlear nucleus (DCN) molecular layer use glutamate as a neurotransmitter. Although metabotropic glutamate receptors (mGluRs) have been identified on cells postsynaptic to the PFs, little is known about the effects of mGluR activation in PF synaptic transmission in the DCN. To investigate these effects, PF-evoked field potentials were recorded from the DCN in guinea pig brain stem slice preparations. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated components of the field response were reversibly depressed by bathing the slice in the mGluR agonists (±)-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD) or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]. A similar depression was produced by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine, but not by the mGluR2/3 agonist (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine or by the mGluR4/6/7/8 agonist l(+)-2-amino-4-phosphonobutyric acid. In addition to the AMPA component, an N-methyl-d-aspartate (NMDA) receptor-dependent component of the field potentials could be identified when the slices were bathed in a low magnesium solution. Under these conditions, the ACPD-induced depression of the AMPA component did not completely recover, whereas the depression of the NMDA component usually recovered and potentiated in some slices. Intracellular recordings of PF-evoked responses were obtained to ascertain which neuronal populations were affected by mGluR activation. Activation of mGluRs produced a reversible depression of PF-evoked responses in cartwheel cells that was not accompanied by any changes in paired-pulse facilitation. The PF-evoked responses recorded from pyramidal cells were unaffected by mGluR activation. Both cell types exhibited a reversible depolarization during (1S,3R)-ACPD application. Subsequent experiments explored the involvement of protein kinases in mediating the effects of mGluRs. The protein kinase C (PKC) activator phorbol-12,13-diacetate partially inhibited the mGluR-mediated depression of the field response;however, the PKC inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide or the protein kinaseA inhibitor N-[2-(( p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide had little effect on the actions of (1S,3R)-ACPD. These results demonstrate that functional mGluRs are present at PF synapses and are capable of modulating PF synaptic transmission in the DCN.

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Facile Synthesis of (2S,1′S,2′S)-2-(Carboxycyclopropyl)glycine, an Isotype-Selective Agonist of Metabotropic Glutamate Receptors

Tetrahedron Letters ◽

10.1016/s0040-4039(97)10037-5 ◽

1997 ◽

Vol 38 (43) ◽

pp. 7599-7602 ◽

Cited By ~ 15

Author(s):

Dawei Ma ◽

Zhaochun Ma

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Facile Synthesis ◽

Metabotropic Glutamate ◽

Selective Agonist

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3,5-Dihydroxyphenylglycine Is a Highly Selective Agonist for Phosphoinositide-Linked Metabotropic Glutamate Receptors in the Rat Hippocampus

Journal of Neurochemistry ◽

10.1046/j.1471-4159.1994.63020769.x ◽

2002 ◽

Vol 63 (2) ◽

pp. 769-772 ◽

Cited By ~ 206

Author(s):

Darryle D. Schoepp ◽

John Goldsworthy ◽

Bryan G. Johnson ◽

Craig R. Salhoff ◽

S. Richard Baker

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Rat Hippocampus ◽

Metabotropic Glutamate ◽

Selective Agonist

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Modulation of mEPSCs in Olfactory Bulb Mitral Cells by Metabotropic Glutamate Receptors

Journal of Neurophysiology ◽

10.1152/jn.1997.78.3.1468 ◽

1997 ◽

Vol 78 (3) ◽

pp. 1468-1475 ◽

Cited By ~ 42

Author(s):

N. E. Schoppa ◽

G. L. Westbrook

Keyword(s):

Olfactory Bulb ◽

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Mitral Cells ◽

Group Iii ◽

Metabotropic Glutamate ◽

Selective Agonist ◽

Group I ◽

Mepsc Frequency ◽

Group Ii

Schoppa, N. E. and G. L. Westbrook. Modulation of mEPSCs in olfactory bulb mitral cells by metabotropic glutamate receptors. J. Neurophysiol. 78: 1468–1475, 1997. Olfactory bulb mitral cells express group I (mGluR1), group II (mGluR2), and group III (mGluR7 and mGluR8) metabotropic glutamate receptors. We examined the role of these mGluRs on excitatory synaptic transmission in cultured mitral cells with the use of whole cell patch-clamp recordings. The effects of group-selective mGluR agonists and antagonists were tested on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor-mediated miniature excitatory postsynaptic currents (mEPSCs). (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylate (ACPD) or the group-I-selective agonist 3,5-dihydroxyphenylglycine evoked an inward current accompanied by a decrease in membrane conductance, consistent with the previously described closure of potassium channels by group I agonists. The increased cellular excitability was accompanied by an increase in mEPSC frequency in some cells. When calcium entry was blocked by cadmium, ACPD or the group-II-selective agonist 2-(2,3-dicarboxycyclopropyl)-glycine reduced the mEPSC frequency. l-2-amino-4-phosphonobutyric acid (l-AP4), a group-III-selective agonist, caused a similar decrease. The concentration-dependence ofl-AP4-mediated inhibition was most consistent with activation of mGluR8. We investigated two possible effector mechanisms for the group III presynaptic receptor. Bath application of forskolin or 3-isobutyl-1-methylxantine had no effect on mEPSC frequency. Increasing calcium influx by raising extracellular K+ caused a large increase in the mEPSC frequency but did not enhance l-AP4-mediated inhibition. Thus inhibition of mEPSCs involves a mechanism downstream of calcium entry and appears to be independent of adenosine 3′,5′-cyclic monophosphate. Our results indicate that both group II and III receptors can inhibit glutamate release at mitral cell terminals. Although group II/III receptors had a similar effect on mEPSCs, differences in location on nerve terminals and in glutamate sensitivity suggest that each mGluR may have discrete actions on mitral cell activity.

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Activity-Dependent Activation of Presynaptic Metabotropic Glutamate Receptors in Locus Coeruleus

Journal of Neurophysiology ◽

10.1152/jn.2000.83.3.1141 ◽

2000 ◽

Vol 83 (3) ◽

pp. 1141-1149 ◽

Cited By ~ 27

Author(s):

G. R. Dubé ◽

K. C. Marshall

Keyword(s):

Dicarboxylic Acid ◽

Locus Coeruleus ◽

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Excitatory Amino Acid ◽

Synaptic Activity ◽

Group Iii ◽

Metabotropic Glutamate ◽

Group Ii ◽

Activity Dependent

Synaptic activation of metabotropic glutamate receptors (mGluRs) in the locus coeruleus (LC) was investigated in adult rat brain slice preparations. Evoked excitatory postsynaptic potentials (EPSPs) resulting from stimulation of LC afferents were measured with current clamp from intracellularly recorded LC neurons. In this preparation, mGluR agonists (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid ( t-ACPD) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) activate distinct presynaptic mGluRs, resulting in an inhibition of EPSPs. When two stimuli were applied to afferents at intervals >200 ms, the amplitude of the second [test (T)] EPSP was identical in amplitude to the first [control(C)]. However, when a stimulation volley was delivered before T, the amplitude of the latter EPSP was consistently smaller than C. The activity-dependent depression (ADD) was dependent on the frequency and duration of the train and the interval between the train and T. ADD was potentiated in the presence of an excitatory amino acid (EAA) uptake inhibitorL- trans-pyrrolidine-2,4-dicarboxylic acid ( t-PDC, 100 μM), changing the T/C ratio from 0.84 ± 0.05 (mean ± SE) in control to 0.69 ± 0.04 in t-PDC ( n = 9). In the presence of t-PDC, the depolarizing response of LC neurons to focally applied glutamate was also increased. Together, these results suggest that accumulation of EAA after synaptic stimulation may be responsible for ADD. To test if ADD is a result of the activation of presynaptic mGluRs, the effect of selective mGluR antagonists on ADD was assessed. In the presence of t-PDC, bath applied (S)-amino-2-methyl-4-phosphonobutanoic acid (MAP4, 500 μM), a mGluR group III antagonist, significantly reversed the decrease in T/C ratio after a train stimulation [from 0.66 ± 0.04 to 0.81 ± 0.02 (mean ± SE), n = 5]. The T/C ratio in the presence of MAP4 was not different from that measured in the absence of a stimulation volley. Conversely, ethyl glutamic acid (EGLU, 500 μM), a mGluR group II antagonist, failed to alter the T/C ratio. Together, these results suggest that, in LC, group III presynaptic mGluR activation provides a feedback mechanism by which excitatory synaptic transmission can be negatively modulated during high-frequency synaptic activity. Furthermore, this study provides functional differentiation between presynaptic groups II and III mGluR in LC and suggests that the group II mGluR may be involved in functions distinct from those of group III mGluRs.

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Differential Regulation of Synaptic Inputs to Dentate Hilar Border Interneurons by Metabotropic Glutamate Receptors

Journal of Neurophysiology ◽

10.1152/jn.1998.79.6.2903 ◽

1998 ◽

Vol 79 (6) ◽

pp. 2903-2910 ◽

Cited By ~ 21

Author(s):

James Doherty ◽

Raymond Dingledine

Keyword(s):

Synaptic Transmission ◽

Glutamate Receptors ◽

Granule Cell ◽

Metabotropic Glutamate Receptors ◽

Cell Layer ◽

Differential Regulation ◽

Granule Cell Layer ◽

Synaptic Inputs ◽

Metabotropic Glutamate ◽

Selective Agonist

Doherty, James and Raymond Dingledine. Differential regulation of synaptic inputs to dentate hilar border interneurons by metabotropic glutamate receptors. J. Neurophysiol. 79: 2903–2910, 1998. Regulation of synaptic transmission by metabotropic glutamate receptors (mGluRs) was examined at two excitatory inputs to interneurons with cell bodies at the granule cell–hilus border in hippocampal slices taken from neonatal rats. Subgroup-selective mGluR agonists altered the reliability, or probability of transmitter release, of evoked minimal excitatory synaptic inputs and decreased the amplitudes of excitatory postsynaptic currents (EPSCs) evoked with conventional stimulation. The group II–selective agonist, (2S,1R′,2R′,3R′)-2-(2,3-dicarboxylcyclopropyl) glycine (DCG-IV; 1 μM), reversibly depressed the reliability of EPSCs evoked by stimulation of the dentate granule cell layer. However, DCG-IV had no significant effect on EPSCs evoked by CA3 stimulation in the majority (82%) of hilar border interneurons. Both the group III–selective agonist, l-(+)-2-amino-4-phosphonobutyric acid (l-AP4; 3 μM), and the group I–selective agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG; 20 μM) reversibly depressed synaptic input to interneurons from both CA3 and the granule cell layer. We conclude that multiple pharmacologically distinct mGluRs presynaptically regulate synaptic transmission at two excitatory inputs to hilar border interneurons. Further, the degree of mGluR-meditated depression of excitatory drive is greater at synapses from dentate granule cells onto interneurons than at synapses from CA3 pyramidal cells.

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Activation of metabotropic glutamate receptors has different effects in different layers of cat visual cortex

Visual Neuroscience ◽

10.1017/s0952523800008786 ◽

1997 ◽

Vol 14 (1) ◽

pp. 83-88 ◽

Cited By ~ 15

Author(s):

Silvia N.M. Reid ◽

Nigel W. Daw

Keyword(s):

Visual Cortex ◽

Dicarboxylic Acid ◽

Glutamate Receptors ◽

Spontaneous Activity ◽

Primary Visual Cortex ◽

Metabotropic Glutamate Receptors ◽

Visual Response ◽

Single Neurons ◽

Metabotropic Glutamate ◽

Cat Visual Cortex

AbstractSingle neurons were recorded in cat primary visual cortex, and the effect of iontophoresis of the metabotropic glutamate agonist 1S,3R-aminocyclopentane-1.3-dicarboxylic acid (ACPD) was observed. In nearly all cases (41/43), ACPD reduced the visual response. In some cases ACPD also reduced spontaneous activity (24/43), and in other cases ACPD increased spontaneous activity (18/43). Increases were generally seen in infragranular layers (V and VI), and decreases in supragranular layers (II and III). The reduction in the visual response was also largest in supragranular layers. We conclude that activation of metabotropic glutamate receptors has both facilitatory and depressive effects in visual cortex, and the effect depends on the layer of the cell recorded.

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