Activation of metabotropic glutamate receptors prevents neuronal apoptosis in culture.
Cultured granule cells grown in serum-containing medium with a "low K+" concentration (10 mM) underwent apoptosis after maturation for 5 days in vitro (5 DIV), a time that coincides with the developmental decline in the activity of metabotropic glutamate receptors (mGluRs) coupled to polyphosphoinositide hydrolysis. The mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) prevented the development of low K(+)-induced apoptosis and the presence of the drug was critical at 6 and 7 DIV, i.e., after the drop of mGluR activity. The neuroprotective action of 1S,3R-ACPD was prevented by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) and was mimicked by N-methyl-D-aspartate or carbamylcholine but not by agonists of the mGluR subtypes negatively linked to adenylyl cyclase. In cultures treated either with Li(+)-which reduced polyphosphoinositide response to concentrations of glutamate (5 microM) that approximate those physiologically present in the incubation medium--or MCPG, the development of low K(+)-induced apoptosis already occurred at 4 DIV. Thus, the activation of mGluRs coupled to polyphosphoinositide hydrolysis by endogenous glutamate could contribute to protect cultured granule cells against apoptosis during early stages of maturation.
Copani
A
A
Institute of Pharmacology and Biochemistry, School of Medicine, University of Catania, Italy.
Bruno
V M
VM
Barresi
V
V
Battaglia
G
G
Condorelli
D F
DF
Nicoletti
F
F
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017470:Receptors, Glutamate / Q000502:physiology*
D005971:Glutamates; D017470:Receptors, Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D011188:Potassium