Neuropeptide Y inhibition of calcium channels in PC-12 pheochromocytoma cells.
We previously demonstrated, using rat PC-12 pheochromocytoma cells differentiated to a sympathetic neuronal phenotype with nerve growth factor (NGF), that neuropeptide Y (NPY) inhibits catecholamine synthesis as well as release. Inquiry into the mechanisms of these inhibitions implicated distinct pathways involving reduction of Ca2+ influx through voltage-activated Ca2+ channels. In the present investigation the effects of NPY on whole cell Ba2+ currents were examined to obtain direct evidence supporting the mechanisms suggested by those studies. NPY was found to inhibit the voltage-activated Ba2+ current in NGF-differentiated PC-12 cells in a reversible fashion with an EC50 of 13 nM. This inhibition was pertussis toxin sensitive and resulted from NPY modulation of L- and N-type Ca2+ channels. The inhibition of L-type channels was not seen with < 1 nM free intracellular Ca2+ or when protein kinase C (PKC) was inhibited by chelerythrine or PKC-(19-31). Furthermore, the effect of NPY on L-type channels was mimicked by the PKC activator phorbol 12-myristate 13-acetate. These studies demonstrate that, in addition to inhibition of N-type Ca2+ channels, in NGF-differentiated PC-12 cells NPY inhibits L-type Ca2+ channels via an intracellular Ca(2+)- and PKC-dependent pathway.
McCullough
L A
LA
Department of Pharmacological and Physiological Science, Saint Louis University Health Sciences Center, Missouri 63104, USA.
Egan
T M
TM
Westfall
T C
TC
D000470:Alkaloids; D000818:Animals; D001464:Barium / Q000037:antagonists & inhibitors / Q000502:physiology; D053119:Benzophenanthridines; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D004553:Electric Conductivity; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009478:Neuropeptide Y / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D037342:Pertussis Toxin; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000470:Alkaloids; D053119:Benzophenanthridines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D009478:Neuropeptide Y; D010617:Phenanthridines; D010566:Virulence Factors, Bordetella; D001464:Barium; C016299:chelerythrine; D037342:Pertussis Toxin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate