Multiple pathways for regulation of the KCl-induced [ 3H]-GABA release by metabotropic glutamate receptors, in primary rat cortical cultures

• Published in: Brain research 1998-01, Vol.782 (1), p.91-104
• Main Authors: Schaffhauser, Hervé, Knoflach, Frédéric, Pink, John Richard, Bleuel, Zaiga, Cartmell, Jayne, Goepfert, Fabienne, Kemp, John A, Richards, John Grayson, Adam, Geo, Mutel, Vincent
• Format: Article
• Language: English
• Subjects: [ 3H]-GABA; Animals; Biological and medical sciences; Blotting, Western; Calcium; Cells, Cultured; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cortical culture; Cyclic AMP - metabolism; Electrophysiology; Fundamental and applied biological sciences. Psychology; gamma-Aminobutyric Acid - metabolism; In Situ Hybridization; Metabotropic; Patch-Clamp Techniques; Potassium Chloride - pharmacology; Rats - embryology; Rats, Inbred Strains; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - physiology; Release; Tritium; Vertebrates: nervous system and sense organs
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(97)01271-7

In rat cortical primary cultures, group II- and III-metabotropic glutamate receptor-selective agonists concentration-dependently reduced KCl-induced [ 3H]GABA release, with IC 50 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 ω-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 In contrast, in the presence of nifedipine, l-AP4 inhibited the remaining [ 3H]GABA release, but LY354740 was no longer active.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 IC 50 values of 28 nM and 22 μM, 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 Ca 2+ channel activity, and the other mediated by group III receptors and possibly involving a regulation located downstream of the Ca 2+ channel activation.