Group I metabotropic glutamate receptors stimulate the activity of poly(ADP-ribose) polymerase in mammalian mGlu1-transfected cells and in cortical cell cultures.
Group I metabotropic glutamate (mGlu) receptors (i.e. mGlu1 and mGlu5) coupled to phospholipase C have been widely investigated for their possible role in excitotoxic and post-ischemic neuronal death. Recently, phospholipase C has been shown to directly stimulate the activity of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair that has been proposed to play a key role in necrotic cell death. In this study, we investigated whether the stimulation of group I mGlu receptors leads to an increase in PARP activity, as detected by flow cytometry, immunodot blot and immunocytochemistry, both in baby hamster kidney cells transfected with mGlu1a or mGlu5a receptors and in cultured cortical cells. Our results show that the group I mGlu receptor agonist DHPG elicited a significant increase in PARP activity that was completely abolished by the administration of the mGlu1 antagonist 3-MATIDA and partially prevented, in cortical neurons, by the mGlu5 antagonist MPEP. To evaluate whether this pathway is involved in post-ischemic neuronal death, we used a sublethal model of oxygen-glucose deprivation in mixed cortical cell cultures. DHPG exacerbated neuronal death, and this effect was significantly prevented by the application of the PARP inhibitor DPQ. This novel pathway may contribute to the effects of mGlu1 receptors in the mechanisms leading to post-ischemic neuronal death.
Meli
Elena
E
Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Viale G. Pieraccini 6, I-50139 Firenze, Italy.
Baronti
Roberto
R
Pangallo
Marilena
M
Picca
Roberta
R
Moroni
Flavio
F
Pellegrini-Giampietro
Domenico E
DE
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D006224:Cricetinae; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000201:enzymology; D007546:Isoquinolines / Q000494:pharmacology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010880:Piperidines / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods
C465380:3-methyl-aminothiophene dicarboxylic acid; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D007546:Isoquinolines; D010880:Piperidines; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013876:Thiophenes; C104077:metabotropic glutamate receptor type 1; C108729:3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone; D008734:Methoxyhydroxyphenylglycol; C121465:6-methyl-2-(phenylethynyl)pyridine; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; D005947:Glucose; C010117:3,4-dihydroxyphenylglycol