The Experts below are selected from a list of 23969466 Experts worldwide ranked by ideXlab platform
Christian Thomsen - One of the best experts on this subject based on the ideXlab platform.
-
Contribution of metabotropic glutamate receptor mGluR4 to L-2-[3H]amino-4-phosphonobutyrate binding in mouse brain.
Journal of neurochemistry, 1999Co-Authors: Christian Thomsen, David R. HampsonAbstract:Abstract : The binding of L-2-[3H]amino-4-phosphonobutyrate ([3H]L-AP4) was examined in brain sections of wild-type mice and mice lacking the mGluR4 subtype of metabotropic glutamate receptors (mGluRs). Very high relative densities of [3H]L-AP4 binding were observed in the molecular layer of the cerebellar cortex, the nucleus basalis, the outer layer of the superior colliculus, and the substantia nigra. In mGluR4 knock-out mice, very low levels of binding were observed in these regions. The moderate levels of binding observed with wild-type mice in the molecular layer of the hippocampal dentate gyrus and in the thalamus were absent in mGluR4 knock-out mice. In contrast, the moderate levels observed in most of the cerebral cortex, caudate putamen, and globus pallidus were not different in mGluR4 knock-out mice compared with wild-type. In these regions, mGluR8 is likely to be labeled by [3H]L-AP4 because mGluR8 is expressed in such brain regions and, like mGluR4, has high affinity for L-AP4. We conclude that mGluR4 contributes substantially to the high-affinity binding site for [3H]L-AP4 in several regions of mouse brain, including cerebellar cortex, nucleus basalis, thalamus, superior colliculus, substantia nigra, and hippocampal dentate gyrus.
-
Autoradiographic visualization of group III metabotropic glutamate receptors using [3H]-L-2-amino-4-phosphonobutyrate
British journal of pharmacology, 1998Co-Authors: Camilla Hudtloff, Christian ThomsenAbstract:In vitro receptor autoradiography using [3H]-L-2-amino-4-phosphonobutyrate ([3H]-L-AP4) binding to sections of rat brain has been characterized and shown to most likely represent labelling of group III metabotropic glutamate receptors. Specific [3H]-L-AP4 binding to rat brain sections was observed at high densities in the molecular layer of the cerebellar cortex and the outer layer of the superior colliculus. Moderate levels were observed throughout the cerebral cortex, in the molecular layer of the hippocampal dentate gyrus, in thalamus, striatum, substantia nigra and in the medial geniculate nucleus. Low levels of [3H]-L-AP4 binding were found in other regions of the hippocampal formation, in the entorhinal cortex and the granule cell layer of cerebellum. Inhibitors of sodium- or calcium/chloride-dependent glutamate uptake did not displace [3H]-L-AP4 binding to rat brain sections indicating that the observed binding does not represent [3H]-L-AP4 uptake via these carriers. Furthermore, in contrast to [3H]-L-AP4 uptake into cerebellar membranes, [3H]-L-AP4 binding to brain sections was sensitive to guanosine-5′-O-(3-thio)trisphosphate-γ-S. In the molecular layer of the cerebellar cortex, [3H]-L-AP4 binding showed a maximal binding density (Bmax) of 0.52±0.06 pmol mg−1 tissue and an affinity (Kd) of 346 nM. The rank order of affinity for displacement of [3H]-L-AP4 binding to rat brain sections was: L-AP4>L-serine-O-phosphate>glutamate>(L)-2-aminomethyl-4-phosphonobutanoate>(1S,3R)-1-aminocyclopentane-1,3-dicarboxylate which is in agreement with a group III metabotropic glutamate receptor pharmacology.
-
The L-AP4 receptor
General pharmacology, 1997Co-Authors: Christian ThomsenAbstract:1. The L-2-amino-4-phosphonobutyric acid (L-AP4) receptor was originally discovered by the ability of L-AP4 to depress synaptic transmission in hippocampal glutamatergic pathways and in the retina. 2. The molecular identity of the L-AP4 receptor is not yet resolved; however, with the molecular cloning of subtypes of metabotropic glutamate receptors (mGluRs), high affinity targets for L-AP4 have been identified. 3. As the information on the pharmacology of the mGluRs and the electrophysiological and biochemical studies on L-AP4 receptor physiology becomes elaborated it seems evident that the L-AP4 receptor is not a single molecular target but may involve multiple receptor subtypes.
-
Phenylglycines can Evoke Quisqualate‐primed Depolarizations in Rat Cingulate Cortex: An Effect Associated with [3H]DL‐AP4 Uptake
The European journal of neuroscience, 1996Co-Authors: Malcolm J. Sheardown, Christian ThomsenAbstract:Depolarization could be evoked in slices of rat cingulate cortex by the normally non-excitatory compound L-2-amino-4-phosphonobutyrate (L-AP4) if the slices had been sensitized by exposure to quisqualate. The magnitude of the response to L-AP4 was dependent on the concentrations of both L-AP4 and quisqualate and was inhibited by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonism. A series of phenylglycine analogues were capable of evoking similar dose-dependent depolarizations in the rat cingulate cortex following quisqualate sensitization, the most potent being (S)-4-carboxy-3-hydroxyphenylglycine. If the superfusate collected during application of (S)-4-carboxy-3-hydroxyphenylglycine to a quisqualate-sensitized slice was administered to a slice not previously exposed to quisqualate, a small depolarization was obtained. All the compounds shown to be capable of evoking the quisqualate-sensitized response showed affinity for the L-AP4 uptake site whilst having no affinity at ionotropic glutamate receptors and different profiles of activity at metabotropic glutamate receptors. None of the compounds was active at the metabotropic glutamate 4a receptor. There was a statistically significant correlation between a compound's effectiveness in inhibiting [3H]DL-AP4 uptake into rat cortical synaptosomes and its potency in evoking quisqualate-sensitized depolarization. It is concluded that this response may be the result of hetero-exchange between L-AP4 ligands and quisqualate.
-
[3H]-L-2-amino-4-phosphonobutyrate labels a metabotropic glutamate receptor, mGluR4a
British journal of pharmacology, 1995Co-Authors: Lisbeth Eriksen, Christian ThomsenAbstract:1. The ligand binding site of subtype mGluR4a of the metabotropic glutamate receptor family was characterized by using [3H]-L-2-amino-4-phosphonobutyrate ([3H]-L-AP4) binding. 2. Specific [3H]-L-AP4 binding to membranes prepared from baby hamster kidney (BHK) cells transfected with a vector encoding mGluR4a accounted for 60-70% of the total binding whereas no specific binding of [3H]-L-AP4 was observed to membranes prepared from BHK cells expressing the vector only. 3. Specific binding of [3H]-L-AP4 to mGluR4a was detectable at 0 degree C, was saturated with 10 min and enhanced by Cl(-)-ions but not by divalent cations (Mg2+, Ca2+, Mn2+). 4. [3H]-L-AP4 binding showed a maximal binding density (Bmax) of 3.0 +/- 0.5 pmol mg-1 protein and an affinity (KD) of 441 nM. A modest decrease in affinity was observed in the presence of 0.1 mM guanosine-5'-O-(3-thio)trisphosphate-gamma-S, the KD being 761 nM and the Bmax 3.4 +/- 0.6 pmol mg-1 protein. 5. The following rank order of affinity for mGluR4a was observed: L-AP4 = L-serine-O-phosphate > glutamate = (2S,1S,2S)-2-(carboxycyclopropyl)-glycine > 1-amino-3-(phosphonomethylene)cyclobitanecar-boxylate > > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate = quisqualate > ibotenate. 6. A highly significant correlation was observed between the potencies of the compounds to inhibit forskolin-stimulated cyclic AMP-formation in BHK cells expressing mGluR4a and the affinity for displacement of [3H]-L-AP4 binding from mGluR4a suggesting that this binding site is functionally relevant. 7. In conclusion, [3H]-L-AP4 is a suitable radioligand for characterizing mGluR4a when expressed in BHK cells. Interestingly, a significant correlation was found between the ability of various compounds to displace [3H]-L-AP4 binding from mGluR4a and the previously observed potencies for inhibition of synaptic transmission via L-AP4 sensitive glutamatergic pathways. These data support the hypothesis that the L-AP4 receptor is contained within the mGluR family.
V Mutel - One of the best experts on this subject based on the ideXlab platform.
-
Effect of the umami peptides on the ligand binding and function of rat mGlu4a receptor might implicate this receptor in the monosodium glutamate taste transduction.
British journal of pharmacology, 1999Co-Authors: Katherine Monastyrskaia, Kenneth Lundstrom, Doris Plahl, Gonzalo Acuna, Christophe Schweitzer, Pari Malherbe, V MutelAbstract:The effect of several metabotropic ligands and di- or tripeptides were tested on the binding of [3H]-L(+)-2-amino-4-phosphonobutyric acid ([3H]-L-AP4) on rat mGlu4 receptor. For selected compounds, the functional activity was determined on this receptor using the guanosine-5′[γ-35S]-thiotriphosphate [γ-35S]-GTP binding assay. Using the scintillation proximity assay, [3H]-L-AP4 saturation analysis gave binding parameters KD and Bmax values of 150 nM and 9.3 pmoles mg−1 protein, respectively. The specific binding was inhibited concentration-dependently by several mGlu receptor ligands, and their rank order of affinity was established. Several peptides inhibited the [3H]-L-AP4 binding with the following rank order of potency: glutamate-glutamate>glutamate-glutamate-leucine=aspartate - glutamate>>glutamate - glutamate-aspartate>lactoyl-glutamate>>aspartate-aspartate. Aspartate-phenylalanine-methyl ester (aspartame) was inactive up to 1 mM and guanosine-5′-monophosphate and inosine-5′-monophosphate were inactive up to 100 μM. The [γ-35S]-GTP binding functional assay was used to determine the agonist activities of the different compounds. For the rat mGlu4 agonists, L-AP4 and L-glutamate, the correlation between their occupancy and activation of the receptor was close to one. The peptides, Glu-Glu, Asp-Glu and Glu-Glu-Asp failed to stimulate the [γ-35S]-GTP binding at receptor occupancy greater than 80% and Glu-Glu-Leu appeared to be a weak partial agonist. These peptides did not elicit a clear dose-dependent umami perception. However, Glu-lac showed a good correlation between its potency to stimulate the [γ-35S]-GTP binding and its affinity for displacement of [3H]-L-AP4 binding. These data are in agreement with the peptide taste assessment in human subjects, which showed that the acid derivatives of glutamate had characteristics similar to umami. British Journal of Pharmacology (1999) 128, 1027–1034; doi:10.1038/sj.bjp.0702885
-
Multiple pathways for regulation of the KCl-induced [3H]-GABA release by metabotropic glutamate receptors, in primary rat cortical cultures.
Brain research, 1998Co-Authors: H Schaffhauser, F Knoflach, J R Pink, Z Bleuel, J Cartmell, F Goepfert, J A Kemp, J G Richards, G Adam, V MutelAbstract:In rat cortical primary cultures, group II- and III-metabotropic glutamate receptor-selective agonists concentration-dependently reduced KCl-induced [3H]GABA release, with IC50 values of 11 nM for LY354740, 80 nM for L(+)-2-amino-4-phosphonobutyric acid (L-AP4), 180 nM for DCG-IV, and 330 nM for L-SOP. The group II antagonists, LY341495 and EGLU, reversed the effect of LY354740, and the group III antagonist MTPG reversed the effect of L-AP4. In the presence of omega-conotoxin GVIA, LY354740 inhibited the remaining [3H]GABA release, whereas L-AP4 was inactive. In contrast, in the presence of nifedipine, L-AP4 inhibited the remaining [3H]GABA release, but LY354740 was no longer active. The PKA inhibitor, H89, blocked the effects of both L-AP4 and LY354740, whereas the PKC inhibitor Ro 31-8220 blocked only the effect of LY354740. Both Ro 31-8220 and H89 reduced the [3H]GABA release to 60% of control. In whole-cell, voltage-clamp experiments, LY354740 and L-AP4 inhibited voltage-gated calcium channel currents with IC50 values of 28 nM and 22 microM, respectively. The results suggest that, in these cells, KCl-induced [3H]GABA release is modulated by two different mechanisms, one involving group II receptors and a direct control of the Ca2+ channel activity, and the other mediated by group III receptors and possibly involving a regulation located downstream of the Ca2+ channel activation.
-
Multiple pathways for regulation of the KCl-induced [3H]-GABA release by metabotropic glutamate receptors, in primary rat cortical cultures
Brain Research, 1998Co-Authors: H Schaffhauser, F Knoflach, J R Pink, Z Bleuel, J Cartmell, F Goepfert, J A Kemp, J G Richards, G Adam, V MutelAbstract:Abstract In rat cortical primary cultures, group II- and III-metabotropic glutamate receptor-selective agonists concentration-dependently reduced KCl-induced [3H]GABA release, with IC50 values of 11 nM for LY354740, 80 nM for l (+)-2-amino-4-phosphonobutyric acid ( l -AP4), 180 nM for DCG-IV, and 330 nM for l -SOP. The group II antagonists, LY341495 and EGLU, reversed the effect of LY354740, and the group III antagonist MTPG reversed the effect of l -AP4. In the presence of ω-conotoxin GVIA, LY354740 inhibited the remaining [3H]GABA release, whereas l -AP4 was inactive. In contrast, in the presence of nifedipine, l -AP4 inhibited the remaining [3H]GABA release, but LY354740 was no longer active. The PKA inhibitor, H89, blocked the effects of both l -AP4 and LY354740, whereas the PKC inhibitor Ro 31-8220 blocked only the effect of LY354740. Both Ro 31-8220 and H89 reduced the [3H]GABA release to 60% of control. In whole-cell, voltage-clamp experiments, LY354740 and l -AP4 inhibited voltage-gated calcium channel currents with IC50 values of 28 nM and 22 μM, respectively. The results suggest that, in these cells, KCl-induced [3H]GABA release is modulated by two different mechanisms, one involving group II receptors and a direct control of the Ca2+ channel activity, and the other mediated by group III receptors and possibly involving a regulation located downstream of the Ca2+ channel activation.
-
L-AP4 inhibition of depolarization-evoked cGMP formation in rat cerebellum
Neuroscience letters, 1997Co-Authors: J Cartmell, J A Kemp, V MutelAbstract:Abstract The effects of the group III mGluR agonist, l -2-amino-4-phosphonobutyrate ( l -AP4), on depolarization-stimulated cGMP levels in adult rat cerebellar slices were determined. l -AP4 elicited a concentration-dependent, complete inhibition of cGMP formation stimulated by 4-aminopyridine (4-AP; 1 mM), yielding an IC 50 value of 4.2±1.6 μ M ( n =3). The 4-AP response was also reduced by the P-type Ca 2+ channel toxins ω -conotoxin MVIIC (3 μ M; 39±7% inhibition) and ω -Agatoxin IVA (30 nM; 53±4%), and was abolished in the absence of Ca 2+ or in the presence of Co 2+ . The inhibitions of the 4-AP cGMP response by 10 μ M l -AP4 and 30 nM ω -Agatoxin IVA were not additive, indicating that part of the actions of l -AP4 in the cerebellum involves the modulation of P-type Ca 2+ channels.
-
Pharmacological characterization of metabotropic glutamate receptors linked to the inhibition of adenylate cyclase activity in rat striatal slices.
Neuropharmacology, 1997Co-Authors: H Schaffhauser, J Cartmell, R. Jakob-røtne, V MutelAbstract:Abstract The pharmacological profile of mGlu receptors negatively linked to adenylyl cyclase was characterized in adult rat striatal slices. Among the mGlu agonists tested, (+)-2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylate (LY354740), was the most potent inhibitor of forskolin-stimulated cAMP formation (EC50 = 11 ± 2nM). Inhibition of forskolin stimulation by the group III agonist L-2-amino-4-phosphono butanoate (L-AP4) was biphasic, the two parts of the concentration curve having EC50 values of 6 ± 1μM and 260 ± 4μM, suggesting a sequential recruitment of mGlu 4 8 and mGlu7. The effects of several new phenylglycine derivative antagonists were tested on the inhibition of forskolin cAMP response by (2S, 1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG I) and l -AP4. At 500 μM, (RS)-α-methyl-3-carboxy-methyl-phenylglycine was unable to antagonize the effect of l -CCG I or l -AP4 but (S)-α-methyl-3-carboxy-phenylalanine inhibited the effect of l -AP4 with a low potency. Finally, (RS)-α-methyl-4-tetrazolylphenylglycine and particularly (RS)-α-methyl-4-phosphonophenylglycine, appeared to be the most potent and selective antagonists of l -AP4 induced inhibition of forskolin-stimulated cAMP production in adult rat striatal slices.
Francine Acher - One of the best experts on this subject based on the ideXlab platform.
-
l 2 amino 4 thiophosphonobutyric acid l thioap4 a new potent agonist of group iii metabotropic glutamate receptors increased distal acidity affords enhanced potency
Journal of Medicinal Chemistry, 2007Co-Authors: Chelliah Selvam, Cyril Goudet, Nadia Oueslati, Francine AcherAbstract:L-2-Amino-4-phosphonobutyric acid (L-AP4), l-2-amino-4-thiophosphonobutyric acid (l-thioAP4), and l-2-amino-4-(hydroxy)phosphinylbutyric acid (desmethylphosphinothricin, DMPT) were synthesized from protected vinylglycine. They were tested as agonists at group III metabotropic glutamate receptors (mGluR) along with phosphinothricin (PT). DMPT and PT display a much lower potency at mGlu4 receptor (EC50 = 4.0 and 1100 microM, respectively) in comparison to L-AP4 (EC50 = 0.08 microM), whereas l-thioAP4 has a 2-fold higher potency (EC50 = 0.039 microM). Similar rank orders of potency were observed at mGlu6,7 and mGlu8 receptors. The higher potency of l-thioAP4 is due to its stronger second acidity compared to L-AP4. These pKa values of 5.56 and 6.88, respectively, were determined using 31P NMR chemical shift variations. The second distal negative charge of L-AP4/l-thioAP4 probably provides stronger binding to specific basic residues of the binding sites of group III mGluRs, which stabilizes the active conformation of the receptor.
-
L-(+)-2-Amino-4-thiophosphonobutyric acid (L-thioAP4), a new potent agonist of group III metabotropic glutamate receptors: increased distal acidity affords enhanced potency.
Journal of medicinal chemistry, 2007Co-Authors: Chelliah Selvam, Jean-philippe Pin, Cyril Goudet, Nadia Oueslati, Francine AcherAbstract:L-2-Amino-4-phosphonobutyric acid (L-AP4), l-2-amino-4-thiophosphonobutyric acid (l-thioAP4), and l-2-amino-4-(hydroxy)phosphinylbutyric acid (desmethylphosphinothricin, DMPT) were synthesized from protected vinylglycine. They were tested as agonists at group III metabotropic glutamate receptors (mGluR) along with phosphinothricin (PT). DMPT and PT display a much lower potency at mGlu4 receptor (EC50 = 4.0 and 1100 microM, respectively) in comparison to L-AP4 (EC50 = 0.08 microM), whereas l-thioAP4 has a 2-fold higher potency (EC50 = 0.039 microM). Similar rank orders of potency were observed at mGlu6,7 and mGlu8 receptors. The higher potency of l-thioAP4 is due to its stronger second acidity compared to L-AP4. These pKa values of 5.56 and 6.88, respectively, were determined using 31P NMR chemical shift variations. The second distal negative charge of L-AP4/l-thioAP4 probably provides stronger binding to specific basic residues of the binding sites of group III mGluRs, which stabilizes the active conformation of the receptor.
James F. Koerner - One of the best experts on this subject based on the ideXlab platform.
-
type 4a metabotropic glutamate receptor identification of new potent agonists and differentiation from the l 2 amino 4 phosphonobutanoic acid sensitive receptor in the lateral perforant pathway in rats
Molecular Pharmacology, 1995Co-Authors: P A Johansen, Rodney L. Johnson, L.a. Chase, A D Sinor, James F. Koerner, Michael B. RobinsonAbstract:Before the discovery of the metabotropic glutamate receptors (mGluRs), the glutamate analogue L-2-amino-4-phosphonobutanoic acid (L-AP4) was identified as a potent presynaptic inhibitor of evoked synaptic transmission in the lateral perforant pathway in rats. The localization and L-AP4 sensitivity of the mGluR4a subtype of mGluRs were consistent with the hypothesis that this receptor mediates the synaptic depressant effects of L-AP4 in the lateral perforant pathway. In the present study, the pharmacology of mGluR4a expressed in baby hamster kidney 570 cells was characterized and compared with that previously reported for the lateral perforant pathway responses. The endogenous excitatory amino acid L-aspartate was inactive at mGluR4a, whereas L-homocysteic acid was only 5-fold less potent than L-glutamate. These data suggest that L-homocysteic acid may be an endogenous agonist at mGluR4a. Of the 30 L-AP4 analogues examined, several compounds were identified as agonists at mGluR4a. The cyclopropyL-AP4 analogue (Z)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid inhibited forskolin-stimulated cAMP production with an EC50 of 0.58 microM, which is comparable to that of L-AP4 (EC50 = 0.43 microM). Two other cyclic analogues of L-AP4 were approximately 10-fold less potent as agonists at mGluR4a, i.e., (+/-)-1-amino-3-(phosphonomethylene)cyclobutanecarboxylic acid (EC50 = 4.4 microM) and (E)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid (EC50 = 7.9 microM). Comparison of the potencies of the compounds for activation of mGluR4a with their potencies for inhibition of lateral perforant pathway responses demonstrates that some compounds have comparable activities in the two systems, whereas several compounds are at least 10-fold more potent in one of the systems. In addition, although the mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine blocked the effects of L-AP4 in the lateral perforant pathway, it did not block the effects of L-AP4 at the cloned receptor. These data provide evidence that mGluR4a does not mediate the effects of L-AP4 in the lateral perforant pathway, they provide new tools to identify the function of these receptors in the mammalian central nervous system, and they indicate that the effects of L-AP4 in the lateral perforant pathway are mediated by a (+)-alpha-methyl-4-carboxyphenylglycine-sensitive receptor.
-
Type 4a metabotropic glutamate receptor: identification of new potent agonists and differentiation from the L-(+)-2-amino-4-phosphonobutanoic acid-sensitive receptor in the lateral perforant pathway in rats.
Molecular pharmacology, 1995Co-Authors: P A Johansen, Rodney L. Johnson, L.a. Chase, A D Sinor, James F. Koerner, Michael B. RobinsonAbstract:Before the discovery of the metabotropic glutamate receptors (mGluRs), the glutamate analogue L-2-amino-4-phosphonobutanoic acid (L-AP4) was identified as a potent presynaptic inhibitor of evoked synaptic transmission in the lateral perforant pathway in rats. The localization and L-AP4 sensitivity of the mGluR4a subtype of mGluRs were consistent with the hypothesis that this receptor mediates the synaptic depressant effects of L-AP4 in the lateral perforant pathway. In the present study, the pharmacology of mGluR4a expressed in baby hamster kidney 570 cells was characterized and compared with that previously reported for the lateral perforant pathway responses. The endogenous excitatory amino acid L-aspartate was inactive at mGluR4a, whereas L-homocysteic acid was only 5-fold less potent than L-glutamate. These data suggest that L-homocysteic acid may be an endogenous agonist at mGluR4a. Of the 30 L-AP4 analogues examined, several compounds were identified as agonists at mGluR4a. The cyclopropyL-AP4 analogue (Z)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid inhibited forskolin-stimulated cAMP production with an EC50 of 0.58 microM, which is comparable to that of L-AP4 (EC50 = 0.43 microM). Two other cyclic analogues of L-AP4 were approximately 10-fold less potent as agonists at mGluR4a, i.e., (+/-)-1-amino-3-(phosphonomethylene)cyclobutanecarboxylic acid (EC50 = 4.4 microM) and (E)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid (EC50 = 7.9 microM). Comparison of the potencies of the compounds for activation of mGluR4a with their potencies for inhibition of lateral perforant pathway responses demonstrates that some compounds have comparable activities in the two systems, whereas several compounds are at least 10-fold more potent in one of the systems. In addition, although the mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine blocked the effects of L-AP4 in the lateral perforant pathway, it did not block the effects of L-AP4 at the cloned receptor. These data provide evidence that mGluR4a does not mediate the effects of L-AP4 in the lateral perforant pathway, they provide new tools to identify the function of these receptors in the mammalian central nervous system, and they indicate that the effects of L-AP4 in the lateral perforant pathway are mediated by a (+)-alpha-methyl-4-carboxyphenylglycine-sensitive receptor.
-
Characterization of retinal and hippocampal L-AP4 receptors using conformationally constrained AP4 analogues.
Brain Research, 1991Co-Authors: N. L. Peterson, Rodney L. Johnson, James F. Koerner, Wallace B. Thoreson, Ron MillerAbstract:Abstract In the past, the absence of useful 2-amino-4-phosphonobutanoic acid (AP4) analogues has hampered the pharmacological study and comparison of different systems which are sensitive to l -AP4. Several conformationally constrained AP4 analogues have now been synthesized: (E)- and (Z)-1-amino-3-phosphonocyclopentanecar☐ylic acid [(E)- and(Z)-cyclopentyl AP4], and (E)- and(Z)-amino-3-phosphonocycolohexanecar☐ylic acid [(E)- and(Z)-cyclohexyl AP4], and the recently synthesized cyclopropyl analogues (E)- and(Z)-2-amino-2, 3-methano-4-phosphonobutanoic acid [(E)-and(Z)-cycloprophy; AP4]. Therefore, we have examined and report here the pharmacology of two retinal and two hippocampal l -AP4 sensitive systems using these analogues. In addition, the pharmacology of two kainic a acid/α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (KAIN/AMPA) pathways and oneN-methyl- d -aspartate (NMDA) hippocampal pathways was examined. We found that the rank order potency of the l -AP4 sensitive systems were similar though not identical. The KAIN/AMPA and NMDA systems had a quite different rank order of potencies than the l -AP4 systems. These data suggest that the l -AP4 receptors in these different systems are structurally similar to each other and differ from both KAIN/AMPA and NMDA receptors.
-
Pre-exposure to L-homocysteinesulfinic acid blocks quisqualate-induced sensitization to L-2-amino-4-phosphonobutanoic acid.
European journal of pharmacology, 1991Co-Authors: Edward R. Whittemore, James F. KoernerAbstract:Quisqualic acid sensitizes hippocampal CA1 neurons to depolarization by L-2-amino-4-phosphonobutanoic acid (L-AP4). This sensitization to L-AP4 is known to be blocked by simultaneous exposure to L-homocysteinesulfinic acid, L-alpha-aminoadipic acid and L-serine-O-sulfate during exposure to quisqualate. We report here that these compounds also act as 'pre-blockers' which, when added and removed from the medium prior to exposure to quisqualate, prevent subsequent induction of sensitization to L-AP4 by quisqualate. This pre-blockade suggests that simple competitive inhibition of extracellular receptor or uptake sites may not be the mechanism by which these compounds attenuate the action of quisqualate in this 'Quis-effect'.
Michael J. Rowan - One of the best experts on this subject based on the ideXlab platform.
-
L-AP4 (l-(+)-2-amino-4-phosphonobutyric acid) induced impairment of spatial learning in the rat is antagonized by MAP4 ((S)-2-amino-2methyl-4-phosphonobutanoic acid)
Behavioural Brain Research, 1996Co-Authors: Christian Hölscher, L Mcglinchey, Michael J. RowanAbstract:Abstract l -AP4, an agonist at the metabotropic glutamate receptors 4, 6, 7, 8 and 9 produced a selective spatial learning impairment in a water maze as well as in an 8-arm maze task when injected i.c.v. (5 gl of a 80 mM solution), a dose previously reported to block consolidation of long-term potentiation in vivo. Acquisition and recall of the spatial water-maze task, as measured by escape latency and quadrant bias, respectively, were impaired, whereas swim speed was not affected. In contrast, ability to perform a non-spatial control task was not impaired; latency to reach a visible escape platform was not delayed in l -AP4-treated animals. No behavioral difference was visible in the open field. MAP4, an antagonist of mGluRs mediating l -AP4 induced reduction of transmitter release, when administered pretraining i.c.v. (5 μl of an 80 mM solution) did not affect motor activity in the open field test but did impair learning of both spatial tasks. In addition, swim speed was increased. However, injecting L-AP4 and MAP4 in combination at equimolar concentrations had no effect on learning in both spatial tasks or on swim speed in the water maze. Neither latency in the visible-platform test nor behavior in the open field was affected. We conclude that l -AP4 sensitive metabotropic glutamate receptors play a selective role in learning and memory formation of the rat.
-
l ap4 l 2 amino 4 phosphonobutyric acid induced impairment of spatial learning in the rat is antagonized by map4 s 2 amino 2methyl 4 phosphonobutanoic acid
Behavioural Brain Research, 1996Co-Authors: Christian Hölscher, L Mcglinchey, Michael J. RowanAbstract:Abstract l -AP4, an agonist at the metabotropic glutamate receptors 4, 6, 7, 8 and 9 produced a selective spatial learning impairment in a water maze as well as in an 8-arm maze task when injected i.c.v. (5 gl of a 80 mM solution), a dose previously reported to block consolidation of long-term potentiation in vivo. Acquisition and recall of the spatial water-maze task, as measured by escape latency and quadrant bias, respectively, were impaired, whereas swim speed was not affected. In contrast, ability to perform a non-spatial control task was not impaired; latency to reach a visible escape platform was not delayed in l -AP4-treated animals. No behavioral difference was visible in the open field. MAP4, an antagonist of mGluRs mediating l -AP4 induced reduction of transmitter release, when administered pretraining i.c.v. (5 μl of an 80 mM solution) did not affect motor activity in the open field test but did impair learning of both spatial tasks. In addition, swim speed was increased. However, injecting L-AP4 and MAP4 in combination at equimolar concentrations had no effect on learning in both spatial tasks or on swim speed in the water maze. Neither latency in the visible-platform test nor behavior in the open field was affected. We conclude that l -AP4 sensitive metabotropic glutamate receptors play a selective role in learning and memory formation of the rat.
-
L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid) induced impairment of spatial learning in the rat is antagonized by MAP4 ((S)-2-amino-2-methyl-4-phosphonobutanoic acid).
Behavioural brain research, 1996Co-Authors: Christian Hölscher, L Mcglinchey, Michael J. RowanAbstract:L-AP4, an agonist at the metabotrophic glutamate receptors 4, 6, 7, 8 and 9 produced a selective spatial learning impairment in a water maze as well as in an 8-arm maze task when injected i.c.v. (5 microliters of a 80 mM solution), a dose previously reported to block consolidation of long-term potentiation in vivo. Acquisition and recall of the spatial water-maze task, as measured by escape latency and quadrant bias, respectively, were impaired, whereas swim speed was not affected. In contrast, ability to perform a non-spatial control task was not impaired; latency to reach a visible escape platform was not delayed in L-AP4-treated animals. No behavioral difference was visible in the open field. MAP4, an antagonist of mGluRs mediating L-AP4 induced reduction of transmitter release, when administered pretraining i.c.v. (5 microliters of an 80 mM solution) did not affect motor activity in the open field test but did impair learning of both spatial tasks. In addition, swim speed was increased. However, injecting L-AP4 and MAP4 in combination at equimolar concentrations had no effect on learning in both spatial tasks or on swim speed in the water maze. Neither latency in the visible-platform test nor behavior in the open field was affected. We conclude that L-AP4 sensitive metabotropic glutamate receptors play a selective role in learning and memory formation of the rat.
