title: Presynaptic inhibition by kainate receptors converges mechanistically with presynaptic inhibition by adenosine and GABAB receptors.
abstract: Kainate receptors are widely reported to regulate the release of neurotransmitter in the CNS, but the mechanisms involved remain controversial. Previous studies have found that the kainate receptor agonist ATPA, which selectively activates Glu(K5)-containing kainate receptors, depresses glutamate release at Schaffer-collateral synapses in the hippocampus. In the present study, we provide pharmacological evidence that this depressant effect is mediated by Glu(K5)-containing heteromers, but is distinct from a similar depressant effect engaged by the kainate receptor agonist domoate. The depressant effect of ATPA is insensitive to antagonists for GABA(A), GABA(B), and adenosine receptors, and is also unaffected by lowering the release probability by reducing extracellular calcium. However, the effect of ATPA is partly occluded by prior activation of GABA(B) receptors and completely occluded by prior activation of adenosine receptors, suggesting a mechanistic convergence of heteromeric Glu(K5) kainate receptor signaling with GABA(B) receptors and adenosine receptors. The effects of domoate are partially occluded by both adenosine and GABA(B) receptor agonists, indicating at least a partial convergence of Glu(K5)-lacking kainate receptor signaling with these other pathways. The depressant effect of ATPA is not blocked by inhibition of serine/threonine protein kinases. These results suggest that ATPA and domoate inhibit glutamate release through mechanisms that converge with those of classical metabotropic receptor agonists, although they do so through different receptors.
authors.affiliation: Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Dara
authors.initials: D
authors.lastname: Partovi
authors.forename: Matthew
authors.initials: M
authors.lastname: Frerking
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000187:drug effects*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D017661:Receptors, Presynaptic / Q000187:drug effects*; D013941:Thymine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000241:Adenosine; D000409:Alanine; D001418:Baclofen; D004791:Enzyme Inhibitors; D018755:GABA Agonists; D018698:Glutamic Acid; D007608:Kainic Acid; D009281:Naphthalenes; D009467:Neuromuscular Depolarizing Agents; D047428:Protein Kinase Inhibitors; D018080:Receptors, GABA-B; D018092:Kainic Acid Receptors; D017661:Receptors, Presynaptic; D013941:Thymine; C509618:1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione; C058819:calphostin C; C012301:domoic acid