(2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl) glycine positively modulates metabotropic glutamate receptors coupled to polyphosphoinositide hydrolysis in rat hippocampal slices.
In rat hippocampal slices, the novel metabotropic glutamate receptor (mGluR) ligand, (1S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) enhanced the stimulation of polyphosphoinositide (PPI) hydrolysis elicited by quisqualate or by submaximal concentrations of ibotenate or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). The enhancing effect of DCG-IV was (i) specific for mGluR agonists, (ii) restricted to hippocampal slice preparation, (iii) reversible, and (iv) not subject to homologous desensitization, in addition, DCG-IV did not interact with L-2-amino-4-phosphonobutanoate (AP4), a noncompetitive antagonist of mGluRs coupled to PPI hydrolysis in brain slices [32]. The action of DCG-IV on quisqualate-stimulated PPI hydrolysis was insensitive to antagonists of ionotropic glutamate receptors and did not appear to be a consequence of a reduction in the intracellular levels of cAMP [14]. When the stimulation of PPI hydrolysis was measured as a function of the incubation time, DCG-IV potentiated quisqualate-stimulated PPI hydrolysis after 60 min of incubation, when quisqualate had already reached its maximal effect. Knowing that activation of protein kinase C (PKC) limits the extent of mGluR agonist-stimulated PPI hydrolysis over time, we have studied the enhancing effect of DCG-IV in the presence of the PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA). As expected [9], TPA reduced quisqualate-stimulated PPI hydrolysis in control slices, but was inactive in slices incubated in the presence of DCG-IV. Taken collectively, these results suggest that DCG-IV positively modulates the activity of mGluRs coupled to PPI hydrolysis through a mechanism, which involves PKC-mediated phosphorylation processes.
Genazzani
A A
AA
Institute of Pharmacology, University of Catania, School of Medicine, Italy.
L'Episcopo
M R
MR
Casabona
G
G
Shinozaki
H
H
Nicoletti
F
F
D000818:Animals; D003521:Cyclopropanes / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism*; D013268:Stimulation, Chemical
D003521:Cyclopropanes; D018129:Phosphatidylinositol Phosphates; D018094:Receptors, Metabotropic Glutamate; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D016318:Quisqualic Acid; D005998:Glycine