Presynaptic GABA(B) receptor modulation of glutamate exocytosis from rat cerebrocortical nerve terminals: receptor decoupling by protein kinase C.
GABA and the GABA(B) receptor agonist (-)-baclofen inhibited 4-aminopyridine (4AP)- and KCl-evoked, Ca2+-dependent glutamate release from rat cerebrocortical synaptosomes. The GABA(B) 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 microg/ml pertussis toxin. As determined by examining the mechanism of GABA(B) 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 GABA(B) receptor activation causing a decrease in synaptosomal excitability. Ionomycin-mediated glutamate release was not affected by (-)-baclofen, indicating that GABA(B) receptors in this preparation are not coupled directly to the exocytotic machinery. Instead, the data invoke a direct coupling of GABA(B) 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.
Perkinton
M S
MS
Department of Pharmacology, Royal Free Hospital School of Medicine, London, England, UK.
Sihra
T S
TS
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism*; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005089:Exocytosis / Q000502:physiology*; D018755:GABA Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D017729:Presynaptic Terminals / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology*; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018080:Receptors, GABA-B; D018698:Glutamic Acid; D015761:4-Aminopyridine; D011493:Protein Kinase C; D001418:Baclofen; D002118:Calcium