title: Activation of neuropeptide Y Y1 receptors inhibits glutamate release through reduction of voltage-dependent Ca2+ entry in the rat cerebral cortex nerve terminals: suppression of this inhibitory effect by the protein kinase C-dependent facilitatory pathway.
abstract: Neuropeptide Y (NPY) is known to regulate the presynaptic glutamate release and neuronal responses to excitatory neurotransmission. The aim of this study was to investigate the effect of NPY on the release of endogenous glutamate from rat cerebrocortical nerve terminals (synaptosomes). NPY inhibited the Ca2+-dependent glutamate release evoked by 4-aminopyridine, and this inhibitory effect was mediated via NPY Y1 receptors, because it was mimicked by the specific NPY Y1 receptor agonist [Leu31 Pro34] NPY and blocked by the NPY Y1 receptor antagonist GR 231118. The inhibitory action of NPY was not due to it decreasing synaptosomal excitability or directly interfering with the release process at some point subsequent to Ca2+ influx, because NPY did not alter the 4-aminopyridine-evoked depolarization of the synaptosomal plasma membrane potential or ionomycin and hypertonic solution-induced glutamate release. Examination of the effect of NPY on the cytosolic [Ca2+] revealed that the inhibition of glutamate release could be attributed to a reduction in voltage-dependent Ca2+ influx. Consistent with this, the NPY-mediated inhibition of glutamate release was completely abolished in synaptosomes pretreated with N- and P/Q-type Ca2+ channel blocker, omega-conotoxin MVIIC. Moreover, NPY-mediated inhibition of 4-aminopyridine-evoked glutamate release was insensitive to KT 5720 and Ro32-0432 but was suppressed when protein kinase C was stimulated with phorbol ester. Together, these results suggest that NPY acting predominantly on NPY Y1 receptors inhibits glutamate release from rat cerebrocortical synaptosomes, likely by a mechanism involving direct coupling of receptors to N- and P/Q-type Ca2+ channels, and this coupling is subject to regulation by protein kinase C-dependent pathway. This implies that selective ligand for NPY receptors may be of value for treatment of conditions characterized by excessive glutamate release in the cerebral cortex.
authors: School of Medicine, Fu Jen Catholic University, 510, Chung-Cheng Road, Hsin-Chuang, Taipei Hsien, Taiwan 24205. med0003@mails.fju.edu.tw
authors: S-J
authors: SJ
authors: Wang
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016257:Fura-2 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D009478:Neuropeptide Y / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: C097287:1229U91; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D009478:Neuropeptide Y; D010456:Peptides, Cyclic; D026902:Potassium Channel Blockers; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D018698:Glutamic Acid; D011189:Potassium Chloride; D015761:4-Aminopyridine; D011493:Protein Kinase C; D002118:Calcium; D016257:Fura-2