Multiple pathways for regulation of the KCl-induced [3H]-GABA release by metabotropic glutamate receptors, in primary rat cortical cultures.
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 In contrast, in the presence of nifedipine, L-AP4 inhibited the remaining [3H]GABA release, but LY354740 was no longer active.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.
Schaffhauser
H
H
Pharma Division Preclinical CNS Research, F. Hoffmann-La Roche, Basel, Switzerland. herve.Schaffhauser@roche.com
Knoflach
F
F
Pink
J R
JR
Bleuel
Z
Z
Cartmell
J
J
Goepfert
F
F
Kemp
J A
JA
Richards
J G
JG
Adam
G
G
Mutel
V
V
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017403:In Situ Hybridization; D018408:Patch-Clamp Techniques; D011189:Potassium Chloride / Q000494:pharmacology*; D051381:Rats / Q000196:embryology; D011919:Rats, Inbred Strains; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018094:Receptors, Metabotropic Glutamate; D014316:Tritium; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D000242:Cyclic AMP