Presynaptic GABAB Receptor Modulation of Glutamate Exocytosis from Rat Cerebrocortical Nerve Terminals: Receptor Decoupling by Protein Kinase C

• Published in: Journal of neurochemistry Vol. 70; no. 4; pp. 1513 - 1522
• Main Authors: Perkinton, Michael S., Sihra, Talvinder S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.04.1998; Blackwell
• Subjects: (−)‐Baclofen; Biological and medical sciences; Ca2+ channels; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Fundamental and applied biological sciences. Psychology; GABAB receptor; Glutamate exocytosis; Protein kinase C; Synaptosomes; Vertebrates: nervous system and sense organs; Cerebral cortex; Protein kinase C; Calcium; Rat; Enzyme; Transferases; Rodentia; Central nervous system; Ionic channel; Exocytosis; Glutamate; Signal transduction; Vertebrata; Synaptosome; Mammalia; Excitatory aminoacid; Neurotransmitter; Gabaergic receptor B; Brain (vertebrata)
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.1998.70041513.x

: GABA and the GABAB receptor agonist (−)‐baclofen inhibited 4‐aminopyridine (4AP)‐ and KCl‐evoked, Ca2+‐dependent glutamate release from rat cerebrocortical synaptosomes. The GABAB receptor antagonist CGP 35348, prevented this inhibition of glutamate release, but phaclofen had no effect. (−)‐Baclofen‐mediated inhibition of glutamate release was insensitive to 2 µg/ml pertussis toxin. As determined by examining the mechanism of GABAB receptor modulation of glutamate release, (−)‐baclofen caused a significant reduction in 4AP‐evoked Ca2+ influx into synaptosomes. The agonist did not alter the resting synaptosomal membrane potential or 4AP‐mediated depolarization; thus, the inhibition of Ca2+ influx could not be attributed to GABAB receptor activation causing a decrease in synaptosomal excitability. Ionomycin‐mediated glutamate release was not affected by (−)‐baclofen, indicating that GABAB receptors in this preparation are not coupled directly to the exocytotic machinery. Instead, the data invoke a direct coupling of GABAB receptors to voltage‐dependent Ca2+ channels linked to glutamate release. This coupling was subject to regulation by protein kinase C (PKC), because (−)‐baclofen‐mediated inhibition of 4AP‐evoked glutamate release was reversed when PKC was stimulated with phorbol ester. This may therefore represent a mechanism by which inhibitory and facilitatory presynaptic receptor inputs interplay to fine‐tune transmitter release.