4-aminopyrrolidine-2-4-dicarboxylic-acid and 1-amino-1-3-dicarboxycyclopentane

Current through voltage-gated calcium channels of rat retinal ganglion cells was recorded using the whole-cell patch-clamp technique. All cells displayed high-voltage-activated currents, and 75% of these also displayed low-voltage-activated (LVA) currents. Currents could be separated on the basis of their voltage/time dependence and sensitivity to nickel ions. The group II metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC; 100 microM) increased LVA current by 40% as did the nonselective mGluR agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (tACPD; 100 microM). Neither the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (100 microM) nor 5-hydroxytryptamine (100 microM) enhanced LVA current. In the presence of (S)-alpha-methyl-4-carboxyphenylglycine (100 microM), a group I/II mGluR antagonist, the tACPD-induced enhancement of LVA current was blocked. The voltage dependence of the activation or inactivation kinetics was unchanged in the presence of tACPD. Inclusion in the pipette solution of GDP-beta-S (1 mM) blocked the enhancement of the LVA current by APDC, whereas GTP-gamma-S (0.5 mM) prevented recovery of the enhancement. The tACPD-mediated enhancement of the LVA current was still present in cells pretreated with pertussis or cholera toxins (500 ng x ml(-1)). Genistein (10 microM) prevented the enhancement of the LVA current. These results suggest that LVA current can be enhanced by activation of mGluR2, by a mechanism that is G-protein dependent and may involve a protein tyrosine kinase step.

Topics: Animals; Calcium; Calcium Channels; Cholera Toxin; Cycloleucine; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Female; Genistein; GTP-Binding Proteins; Kinetics; Male; Membrane Potentials; Neuroprotective Agents; Patch-Clamp Techniques; Pertussis Toxin; Proline; Rats; Rats, Inbred Strains; Receptors, Metabotropic Glutamate; Retinal Ganglion Cells

Although the contractile effects of glutamate and related excitatory amino acids on gut smooth muscle strips have been demonstrated, the mechanisms, and particularly the physiological importance of that action, remain unknown. In this study, glutamate, aspartate, AMPA, quisqualate, cis-ACPD and (2R,4R)-APDC evoked concentration-dependent contraction of isolated adult rat gastric fundus, with EC50 values of 210 microM, 150 microM, 20 microM, 33 microM, and 2.7 microM and 7.9 microM, respectively. L-SOP (0.1 microM-1.9 mM) did not change the basal tone of the preparations. The maximal contractions evoked by glutamate (20 mM) were 38.83% compared with those elicited by acetylcholine (20 microM). The glutamate-evoked contractions were not affected by atropine, verapamil and nicardipine, blocked by CNQX (0.01 microM), or potentiated by Mg2+ (0.01-100 microM), ketamine (0.01-100 microM) and DL-AP5 (0.1-100 microM), as well as L-trans-2,4-PDC (1-100 microM). Analysis of glutamate's action on rat rectum (EC50 = 44 microM) could only be carried out at the early stages, as half of the preparations were not affected by glutamate. Only 5 out of 26 human longitudinal and circular smooth muscle preparations taken from the stomach and three segments of the large intestine were very slightly contracted by glutamate, excluding further analysis. The contractile effects of glutamate on rat gut smooth muscles were mediated by multiple GluR (non-NMDA > NMDA > group I/II mGluRs) located primarily on smooth muscle cells but functional GluRs on neurons and/or nerve fibers of myenteric nervous plexuses could not be excluded. To fully understand the physiological significance of glutamate-evoked contractions in the gut, more research is required, most likely using many different methodological approaches.

Topics: Aged; Animals; Aspartic Acid; Cycloleucine; Evoked Potentials, Motor; Female; Gastric Fundus; Glutamic Acid; Humans; In Vitro Techniques; Intestine, Large; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Proline; Quisqualic Acid; Rats; Receptors, Glutamate; Rectum; Stomach

Striatal function is heavily influenced by glutamatergic and dopaminergic afferent input. To ultimately better understand how the N-methyl-D-aspartate (NMDA) antagonist, phencyclidine (PCP), alters striatal function, we sought to determine how NMDA receptor function is influenced by activation of other glutamatergic receptors and by dopaminergic receptors. To this end, we used NMDA-stimulated efflux of [14C]GABA and [3H]acetylcholine (ACh) from striatal slices to assess the influence of these receptors on NMDA function. NMDA-stimulated [14C]GABA release was more sensitive to NMDA and glycine antagonists than was [3H]ACh release, suggesting that different NMDA receptors regulate the release of these neurotransmitters. Furthermore, NMDA-stimulated [3H]ACh release was inhibited by a D2 receptor mechanism whereas NMDA-stimulated [14C]GABA release was enhanced by D1 receptor activation. NMDA and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) interact additively to evoke [3H]ACh release, and synergistically to evoke [14C]GABA release. An additive effect of NMDA and kainate (KA) was found on [14C]GABA release, but NMDA and KA acted in a less than additive manner in evoking [3H]ACh release. KA-stimulated [3H]ACh release was largely blocked by NMDA antagonists, suggesting mediation through activation of NMDA receptors, probably secondary to KA-induced glutamate release. A selective group II metabotropic receptor agonist inhibited NMDA-stimulated [14C]GABA and [3H]ACh release. On the other hand, NMDA-stimulated [14C]GABA release was potentiated by activation of group I metabotropic receptors. Thus, in addition to the differential modulation by D1- and D2-like receptors, the release of striatal neurotransmitters by NMDA receptor activation depends on the extent to which the other glutamate receptors, both ionotropic and metabotropic, are activated.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Acetylcholine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzoates; Carbon Radioisotopes; Corpus Striatum; Cycloleucine; Dopamine Agonists; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Glycine; Kainic Acid; Male; N-Methylaspartate; Proline; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Tritium

The mGlu receptor subtypes and second messenger pathways that mediate 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) responses in brain tissues are not fully understood. 1S,3R-ACPD differs from 3,5-dihydroxyphenylglycine (DHPG) or quisqualate in that 1S,3R-ACPD also activates group 2 mGlu receptors (mGlu2 and mGlu3) that are negatively linked to cAMP formation. To investigate the contribution of group 2 mGlu receptor activity of 1S,3R-ACPD to the phosphoinositide response in the rat hippocampus, we examined the effects of the novel group 2 mGlu receptor agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC). 2R,4R-APDC did not activate or inhibit group 1 mGlu receptors (human mGlu1 alpha and mGlu5a) or group 3 mGlu receptors (human mGlu4 and mGlu7), but potently decreased forskolin-stimulated cAMP formation in human mGlu2- and mGlu3-expressing cells. In slices of the adult rat hippocampus 2R,4R-APDC had no effect on basal phosphoinositide hydrolysis; however, it was found to greatly enhance phosphoinositide hydrolysis to DHPG or quisqualate. In the neonatal rat hippocampus, 2R,4R-APDC enhanced the potency of DHPG, while not affecting the maximal response to group 1 mGlu receptor agonists. Thus, the phosphoinositide response in the rat hippocampus to 1S,3R-ACPD is mediated by a synergistic interaction between group 1 and group 2 mGlu receptors.

Topics: Aging; Animals; Animals, Newborn; Brain; Cloning, Molecular; Colforsin; Cyclic AMP; Cycloleucine; Drug Synergism; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Hippocampus; Humans; Inositol; Kinetics; Neuroprotective Agents; Phosphatidylinositols; Proline; Quisqualic Acid; Rats; Receptors, Metabotropic Glutamate; Recombinant Proteins; Resorcinols; Second Messenger Systems